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Small Molecule Highlights #24 – April 2024

Small Molecule Highlights #24 – April 2024

In this issue of “Small Molecule Highlights” we bring you 5 new small molecules out of recent drug discovery journals. These molecules target a diverse selection of targets, including RXFP1, BRD4, eIF2B, and PKa. Enjoy!



AZ7976:  Scientists at AstraZeneca and the Mitsubishi Tanabe Pharma Corporation have recently published a set of papers detailing their hit-to-lead and lead optimization efforts towards the development of AZ5462, a small molecule agonist of the relaxin family peptide receptor 1 (RXFP1).  Their hit-to-lead work leading to AZ7976 will be discussed here.  Agonism of RXFP1 has garnered a significant amount of attention over the past decade, especially for the treatment of heart failure.  However, discovery of new agonists has been met with great difficulty.  Both AstraZeneca and GSK (10.1038/s41598-017-10521-9) were recently unsuccessful in identifying chemical starting points via HTS of their internal compound collections.  Furthermore, GPCRs, such as RXFP1, are notoriously flexible and contain multiple binding sites making structure-based drug design approaches challenging.  Drug development thus far has relied on ML290, a small molecule allosteric agonist discovered by the NIH Chemical Genomics Center, as a starting point.  The research team quickly identified issues with solubility, lipophilicity, and plasma protein binding (PPB) leading to terrible early dose to man (eD2M) predictions (37g/day/70 kg).  With the goal of attaining a nanomolar agonist with an eD2M below 500 mg/kg, the team performed a comprehensive SAR study to optimize the parent scaffold.  One of the most structurally conspicuous alterations was the incorporation of the central norbornane.  This was done to break the planarity enforced by the previous phenyl substituent, allowing for greater solubility and lower clearance whilst maintaining activity.  The terminal cyclohexyl carboxylic acid provided the largest impact across all the parameters considered (activity, solubility, lipophilicity, and clearance).  As carboxylic acids are often susceptible to clearance via conjugation, a closely situated methyl group was installed to protect this functional group from metabolism.  The pentafluorosulfur substituent offered a substantial boost in activity (more than 2-orders of magnitude), counterbalancing the poor metabolic profile of the compound and reducing eD2M to 60mg/day/70kg.  In a receptor selectivity panel (Eurofins), AZ7976 exhibited exquisite selectivity for RXFP1 (> 5000-fold selectivity vs the rest of the panel).  Interestingly, an enantiomer of the compound was poorly selective, owing to its greatly reduced activity against RXFP1 (10,000-fold less potent than AZ7976).  To probe binding, a radiometric competition assay against relaxin-H2 provided further support for an allosteric binding mechanism leading to protein agonism.  In an in vivo setting, target engagement and pharmacodynamic effect was demonstrated in anesthetized rats.  Both AZ7976 and its inactive stereoisomer were benchmarked against relaxin-H2.  In the study, AZ7976 exhibited durable modulation of heart rate and mean blood pressure, similar to the short-lived increases in both parameters observed in the relaxin-H2 treated cohort.  As the inactive compound did not show any effect, direct agonism of RXFP1 by AZ7976 could be inferred.  In scope, AZ7976 looks like a very promising lead optimization candidate.  While activity and selectivity has been dialed in, more work must be done to address low solubility, high lipophilicity, and poor PK.

Reference: https://doi.org/10.1021/acs.jmedchem.3c02183



AZD5462:  Building on AZ7976 (vide supra), the AstraZeneca and Tanabe Pharma team aimed to improve the physicochemical properties and pharmacokinetic profile of this lead compound.  As with most lead optimization endeavours, compromises had to be made to strike the right balance between PK and activity to enable clinical development.  Fortuitously, AZ7976 was exceedingly potent (hRXFP1cAMP pEC50 = 9.4), allowing for much more rigorous exploration of chemical space to tune the desired properties.  Overtly, the only change made was a swap of the pentafluorosulfur aniline to a cyclized neopentyl amine, however, every portion of the molecule, other than the norbornane core, was subject to optimization.  For instance, the terminal carboxylic acid was replaced by a variety of mimics to circumvent racemization of the carbon attached to the group.  Also, modifications to the fluorine substituent on the central phenyl ring were found to modulate activity.  Interestingly, replacement with a cyano group increased activity by more than 10-fold.  Circling back to replacement of the penatafluorosulfur aniline, this was a practical decision made out of necessity.  The group was much too lipophilic and posed a potential genotoxicity risk (aniline group).  The researchers settled on a substituent that was lipophilic enough to maintain binding interactions with the target whilst decreasing the planarity of the molecule.  Pharmacokinetic characterization of AZD5462 revealed moderate oral bioavailability (F = 47%) and good plasma half-life (T1/2 = 4.6 h) in rat.  Multiple assays assessing cardiac (hERG, Nav1.5 and Kv4.3 IC50 > 40 μM) and liver (BSEP IC50 = 7.1 μM) safety, as well as genotoxicity (negative Ames and A549 micronuclei tests),  indicated no potential safety concerns.  As was done with AZ7976, hemodynamic changes (heart rate and mean blood pressure) in rat were evaluated using AZD5462 and an inactive diastereomer.  In this way, any effects observed could be ascribed to RXFP1 inhibition.  In the study, AZD5462 activity surpassed that of the positive control (relaxin H2).  Pharmacodynamic characterization in a disease relevant model (obese cynomolgus monkeys exhibiting heart failure) revealed statistically significant improvements in left ventricle ejection fraction (LVEF) that was sustained 13 weeks post administration in both dosing regimes tested (1 mg/kg q.d and 10 mg/kg b.i.d).  With such promising results, AZD5462 has progressed into clinical evaluations in healthy volunteers (NCT04994106, NCT05512806, and NCT05395117) and has recently been linked to, although not recruiting, a Phase IIb study in patients with chronic heart failure (LUMINARA; NCT06299826).                      

Reference: https://doi.org/10.1021/acs.jmedchem.3c02184

CURE-PRO 55 + 63

CURE-PRO 55 + 63
CURE-PRO 55 + 63

CURE-PRO 55 + 63:  A very interesting targeted protein degrader (TPD) development platform has recently been disclosed by researchers at Cornell University (USA).  In an effort to resolve solubility and permeability issues often associated with PROTACs, the group leveraged their Coferon technology to develop self-assembling degraders.  The  principle is elegant and simple, use bio-orthogonal linker chemistries to unite protein of interest (POI) and E3-ligase recruiter ligands within the cell.  The benefits are obvious; no “hook effect” at higher concentrations (significantly increases dosage window compared to PROTACs) and improved drug-like properties owing to smaller compound size.  If that wasn’t enough to win over the most ardent ternary PROTAC supporters, a very clever acronym for the platform surely will; CURE-PROs (Combinatorial Ubiquitination REal-time PROteolysis).  As a proof-of-concept, the medicinal chemistry team prepared a CURE-PRO targeting BRD4 using a catechol and boronic acid as the bio-orthogonal linker pair.  Slight optimization of the catechol regiochemistry was required to fully dial in activity.  Dose-dependant degradation of BRD4 was demonstrated in MCF7 cells (DC50 = 358 nM) and in a real-time kinetic degradation study using HiBiT-BRD4 KI HEK293 (LgBiT) cells.  As was mentioned previously, no “hook effect” was observed at the highest concentration tested (10 μM) permitting durable degradation for sustained periods, even after wash-out.  It bears mentioning that the stoichiometry of the POI ligand and E3-ligase recruiter doesn’t have to be 1:1 to enable protein degradation.  Various stoichiometries of CURE-PRO ligand pairs were shown to be effective. Pharmacokinetic characterization of 55 and 63 revealed rapid absorption of both molecules (Tmax = 0.5 h), however, 63 was shown to be removed from circulation much more quickly than 55, potentially by extrahepatic clearance and renal filtration.  Pharmacodynamic efficacy was demonstrated in an MV4-11 xenograft model in mice.  In the study, significantly reduced BRD4 levels were observed in tumor samples across multiple time-points, aligning well with in vitro findings.  The real beauty of the platform is its ability to discover novel degraders using combinatorial screening.  In this approach, a variety of E3 recruiters with varying catechol linkers can be quickly assessed against POI ligands containing variations of the corresponding boronic acid partner, allowing for rapid identification of PROTAC starting points without protracted SAR studies/campaigns.  Currently, the CURE-PRO platform has a variety of E3-recruiter fragments targeting VHL, CRBN, and even MDM2.  It will be interesting to see how the platform  evolves.  We predict we will be seeing a covalent E3 recruiter CURE-PRO fragment in the near future.        

Reference: https://doi.org/10.1021/acs.jmedchem.3c02097



DNL343: The integrated stress response (ISR) is an adaptive signalling pathway regulating protein homeostasis and promoting overall survival in response to cellular insult(s).  While the pathway’s cytoprotective role is very much context specific (agonism and antagonism of the pathway has been shown modulate survival), a growing body of evidence has implicated chronic activation of ISR in a range of neurodegenerative diseases, such as vanishing white matter (VWM) disease and amyotrophic lateral sclerosis (ALS).  The drug development team at Denali Therapeutics have targeted a crucial nucleotide exchange factor (eIF2B) in the pathway.  To support structure-based drug design endeavors, the team built a homology model of human eIF2B using a homologous protein found in yeast. Further scanning mutagenesis studies were used to identify the putative binding site with the help of ISRIB (a previously published inhibitor of the eIF2B).  Discovery efforts were also supported by a substantial HTS screening campaign of approximately 400,000 compounds.  Lead development hinged on the optimization of properties promoting CNS penetration.  Towards this end, an oxadiazole substituent replaced a secondary amide group to lessen active transport of the compound out of the CNS via Pgp mediated efflux.  Also, the sp3 character and solubility was greatly increased by limiting the arene content of previous congeners by incorporating a cyclobutyltrifluoromethyl ether in its place.  Pharmacokinetic characterization of DNL343 revealed impressive oral bioavailability (F(%) = 65/>99/>99 in rat/dog/monkey) and plasma half-life (T1/2(h)= 12.5/7.4/7.6 in rat/dog/monkey) across species.  Also, passage into the CNS was relatively high with brain-to-plasma ratios of 0.8 and 0.9 being observed in rat and monkey, respectively.  No risks associated with drug-drug interactions (DDI), genotoxicity/mutagenicity (negative AMES and micronuclei tests), and cardiac toxicity were flagged in follow up safety studies.  In vitro characterization of the compound in an H4 cellular model of ALS confirmed potent suppression of sodium arsenite mediated stress granule formation via the ISR pathway (IC50 = 13 nM).  Pharmacokinetic efficacy was evaluated in a mouse model of ISR driven neurodegenerative disease (Eif2b5 R191H mice).  In the study, DNL343 was found to significantly decrease ISR transcript markers in the brain.  DNL343 has made its way into phase I and Ib clinical trials in healthy (NCT04581772) and ALS stricken individuals (NCT05006352), respectively.  Results from the trial indicated fairly consistent PK with predictable dose/exposure correlations.  Multicenter phase II and III studies are currently recruiting/enrolling participants (NCT05842941 and NCT04297683).

Reference: https://doi.org/10.1021/acs.jmedchem.3c02422

Compound 20

Compound 20
Compound 20

Compound 20:  Researchers at KalVista Pharmaceuticals and the University of Nottingham have recently disclosed their preliminary medicinal chemistry efforts to develop a covalent inhibitor for plasma kallikrein (PKa) protein.  PKa is a serine protease involved in the bradykinin (BK) signaling which impacts the homeostasis of blood vessels.  Dysregulation of BK can lead to increased vasodilation and blood vessel leakage, with severe cases resulting in systemic angioedema.  While a variety of small molecule treatment options (berotralstat and sebetralstat) are available, none are irreversible, possibly pointing to difficulties in developing a covalent inhibitor for this particular target.  Using a structure-based drug design approach, the team was able to identify a scaffold and potential attachment points for a covalent warhead (WH) targeting Ser195.  The chosen warhead, a pinacol-boronic ester, comes as no surprise as boronic acids are ideally suited for engaging serine’s hydroxy sidechain as a result of its Lewis acidic nature.  Iterative rounds of SAR led to compound 20 which demonstrated superb time-dependant inhibition of PKa (IC50 = 66/6.9/0.3 nM @ 1/10/60 min) and exquisite selectivity over closely related proteases (>1000-fold selectivity).  The activity of 20 was curious as molecular docking studies had failed to orient the rather large pinacol boronate  within the Ser195 sub-pocket.  Fortunately, some key observations made during the synthesis of related compounds were able to shed some light on the mystery; the pinacol boronate was prone to hydrolysis.  As such, the active compound was likely a boronic acid or the corresponding cyclization product with the adjacent amide oxygen (oxaborolane).  NMR studies carried out in PBS buffer confirmed cleavage of the pinacol to afford the corresponding boronic acid and oxaborolane which exist in equilibrium. While no further ADME, PK, or PD studies were carried out, presumably due to the labile nature of the WH contributing to synthesis and purification difficulties, compound 20 adds valuable insights into the use of amidoboronates as covalent WHs, especially in the serine protease inhibitor space.

Reference: https://doi.org/10.1021/acsmedchemlett.3c00572

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Taleb Sedighi, PhD

Director of Proteomics and Protein MS

Taleb is a distinguished scholar with a PhD in Bioanalytical Chemistry from Simon Fraser University in Canada, complemented by an MSc and BSc in Analytical Chemistry. With a robust 16 years of experience, Taleb’s expertise lies in utilizing mass spectrometry techniques for the analysis of proteins and small molecules.

Since joining Dalriada in January 2021, Taleb has led the development of innovative platforms in chemoproteomics and covalent hit identification cascade, which have significantly contributed to over 20 covalent and targeted protein degradation programs.

Before joining Dalriada, Taleb was a Research Associate at the Patrick Gunning lab at the University of Toronto, where he played a pivotal role in establishing various proteomics and DMPK methods crucial for supporting early drug discovery programs.

Beyond his professional accomplishments, Taleb’s passion for science and research is evident, underscored by his authorship of 46 publications and numerous contributions to patent filings and grant proposals.

Pegah Ghiabi, PhD

Associate Director, Protein Production

Pegah brings over 25 years of extensive experience in biomedical research and leadership, Pegah brings a wealth of expertise in cancer research, protein science, and drug discovery within academic settings.

Prior to joining Dalriada, Pegah served as a senior research associate and Head of the protein production core facility at the Structural Genomics Consortium (SGC), University of Toronto. In this role, she provided strategic guidance and supervision for generating protein targets crucial to numerous drug discovery projects, collaborating with both academic and industry partners. Notable collaborations included projects with Nurix Therapeutics, Pfizer, Bristol Myers Squibb, Takeda, Merck KGaA, Janssen, Novartis, and X-Chem.

As a leader of the protein production team, Pegah brings unparalleled expertise in human and viral protein production. Her proficiencies span target selection, construct design, expression vector selection, protein expression across bacterial, insect, and mammalian systems, protein purification, and biophysical approaches for protein quality assessment. Pegah boasts extensive experience across various target classes, including helicases, proteases, methyltransferases, exonucleases, E3 ligases, polymerases, the WDR protein family, and structural proteins in both human and viruses.

Pegah holds an MSc in Cell Biology from McGill University, Canada, and a PhD in Cellular and Molecular Biology from the University of Paris-Sud (XI), France. After her doctoral studies, she undertook a postdoctoral position at Weill Cornell University in the USA.

Chris Yarnold, PhD

Director, Discovery Chemistry

Chris brings over 20 years’ industrial integrated discovery, medicinal chemistry and project leadership experience.

Prior to joining Dalriada, Chris spent 20+ years at Evotec (UK) as Group Leader in Medicinal/Discovery Chemistry where he was Project Leader for drug discovery projects covering a broad range of Therapeutic Areas and was Global Medicinal Chemistry contact for Metabolic Diseases.

Chris has experience as Project Leader in major disease areas including Cardiovascular, Oncology, CNS and Metabolic diseases.  Additionally, Chris has led anti-infective, iron overload disease and anti-thrombotic collaborations. His expertise includes hit finding and expansion, Hit-to-Lead and Lead Optimization preclinical phases. Three clinical candidates were identified. FV-100 has reached PhIII for shingles, Vamifeport is progressing through PhIIa for iron overload diseases and ONO-7684 is currently in PhI trials as a novel antithrombotic agent.  He has experience in targeting enzymes, GPCRs and transporters with small molecules. Chris has extensive experience of managing teams, encouraging and developing chemists to reach their full potential.

Chris has a B.Sc (Joint Hons) in Chemistry and Biology and a Ph.D. from King’s College London. Chris gained postdoctoral experience with Professor Walter Szarek at Queen’s University, Kingston, Canada and Professor Chris McGuigan at the Welsh School of Pharmacy, Cardiff.

Kaushik Ghosal, PhD

Head of BD, North America

Kaushik Ghosal is a successful entrepreneur and business development executive with over 15 years of bio-pharma experience in a variety of R&D and BD roles across several verticals in R&D business models, corporate expansion and strategic leadership in drug discovery and early development. Most recently Kaushik was Director of BD at Evotec (NASDAQ: EVO) leading partnered drug discovery and development programs for both stand alone and integrated drug discovery projects for several small and large biotechs, drug development accelerators and large pharma clients. 

​Prior to Evotec, Kaushik was the Director of Business Development at BioMotiv where he was instrumental in launching and leading a portfolio of venture-backed biotechs such as Sujana Bio, Optikira, Koutif Therapeutics. During his tenure, BioMotiv and Harrington project grew into a 360M + global initiative and established strategic partnerships with Takeda, Biogen, Arix Bioscience and Charles River Laboratories. At BioMotiv, Kaushik also founded therapeutic focused start-ups such as BioExcel and Inclera therapeutics to advance academic sourced drug discovery programs, some of which developed into clinical stage assets.

Before BioMotiv, Kaushik was Director of R&D at ReXceptor Inc, a clinical stage biotech company where he led preclinical and clinical development, establishing strategic partnerships with pharmaceutical companies and drug-development accelerators. 

Kaushik received MSc in Biotechnology (Indian Institute of Technology, Bombay), a Ph.D. from Miami University and completed his postdoctoral training in Neuroscience from the Cleveland Clinic. Kaushik has served on various advisory and on the boards of non-profit and for-profit organizations in the healthcare field such as NIH, John Hopkins Technology Ventures, EDI and Case Venture Mentorship Program.

Richard Rathmell, PhD

SVP Discovery Chemistry

Rich is Dalriada’s SVP Discovery Chemistry, responsible for scientific strategy of programs in discovery chemistry and a key contributor to the continuous R&D capability build at Dalriada. He brings 23 years of discovery experience, medicinal chemistry, and project leadership working at Eli Lilly and most recently Evotec, in the UK.  

Before joining Dalriada, Rich was Vice President and Head of a Chemistry Department at Evotec UK, where he held strategic and scientific direction oversight for a portfolio of pain and metabolic disorder programs. He helped to shape the vison and direction of the chemistry group and additionally was a key contributor developing new screening strategies, and designing associated libraries, for early phase projects.

Prior to Evotec, Rich gained exceptional experience in integrated drug discovery with a 20+ year career at Eli Lilly UK. He held the positions of Group Leader and Research Advisor, where he had oversight for the portfolio management of his team. Scientifically, Rich has been involved in 25+ integrated drug discovery programs across neurosciences, pain, and metabolic disorders. His expertise spans all stages of drug discovery, from target identification and validation to Hit-to-Lead and Lead Optimization, culminating in the delivery of 8 clinical candidates, two reaching PhI and one still progressing through PhIIa for Alzheimer’s disease. He is familiar with multiple modalities, from small molecules, protein-protein interactions, protein degradation, protein translation inhibition and peptides. He brings extensive experience with target classes such as GPCRs, enzymes, transporters, and ion channels.

Rich has a B.Sc (Hons) and a Ph.D in Chemistry from the University of Exeter UK, before taking up a postdoctoral position working with the late Sir Jack Baldwin at the University of Oxford.

Adam Davenport

Adam Davenport, PhD

Chief R&D Officer

Adam is Dalriada’s Chief R&D Officer. A seasoned drug hunter and innovator, he brings over 22 years of hands-on life science and partnership organization experience, having contributed to drug candidates and clinical assets through both governance and leadership roles.

Prior to Dalriada, Adam’s outstanding career was spent at Evotec, then Oxford Asymmetry International, which he joined in 2001. There, he gained extensive experience from Hit ID through to IND, across diverse modalities, target classes (GPCRs, ion-channels, PPIs, CNS, kinases, enzymes) and therapeutic areas (pain, inflammation, cognition, metabolic, Women’s Health and respiratory).

As a Project Leader, Adam has progressed multiple projects through Discovery into Clinical evaluation and is lead inventor of P2X3R antagonists Eliapixant and Filopixant, achieving Phase 2a PoCs in Persistent Chronic Cough (PCC), and Bradykinin B1R antagonist Fulimetibant, undergoing a Phase 2a study to treat diabetic neuropathic pain (DNP).

Adam’s promotion to VP Medicinal Chemistry saw him take on scientific and strategic portfolio responsibilities as well as operational duties in Abingdon, UK. Progression through Senior to Executive VP expanded Adam’s leadership and strategic influence on the organisation, where he established and led as Head of Global Molecular Discovery, a multi-modality data-driven Design and Synthesis function based in the UK, FR, IT and US.

Passionate about science and communication, Adam has authored over 55 patents, publications and external presentations and was co-recipient of the Bayer Healthcare Drug Discovery Award for Collaborative Innovation in 2017.

Adam holds a B.Sc. Honours degree in Chemistry and a PhD in Organometallic Chemistry from the University of Leicester, UK.

Frosty Loechel, PhD

SVP Biology

Frosty is Dalriada’s Head of Biology, responsible for the scientific strategy of the discovery program in biology and a key contributor to the continuous evaluation of our scientific capabilities, operations, and infrastructure. He brings 20 years’ academic experience and 25 years working in pharma, biotech, and CROs.

Before joining Dalriada, Frosty gained exceptional experience in discovery programs at Evotec. First as a VP, Metabolic diseases, he built up a large department running iPSC work, in vitro pharmacology, advanced cellular platforms, transcriptomics, imaging, and data science. Then, as SVP, Therapeutic Area Lead and Scientific Director, he led on new collaborative drug discovery agreements with pharma/biotech partners and on the strategy of project portfolio in major multi-target collaborations.

Prior experience includes work at Zealand Pharma, where he focused on peptide drugs for a portfolio of diabetes and obesity projects. His earlier career was spent at Lundbeck, Thermo Fisher, Neurosearch and BioImage, where he gained a strong background in a broad spectrum of scientific areas.

Frosty has been involved in hundreds of drug discovery projects and gained a wealth of experience across multiple areas and therapeutic modalities including CNS and metabolic diseases. His expertise spans all stages of drug discovery, from target identification and validation to Hit-to-Lead and Lead Optimization, and nomination of preclinical candidates. He is familiar with multiple modalities, from small molecules, to peptides, to biologics, and brings extensive experience with target classes such as GPCRs, kinases, transporters, ion channels and proteases.

Frosty has a B.A. in Biochemistry from the University of Kansas, and a Ph.D. from the Faculty of Health Sciences of the University of Copenhagen. He is a Danish citizen and is fluent in English, Danish, and Italian.

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Brian Sequeira

Brian Sequeira

Director, Information Systems, PMO

As Director of Information Systems and PMO, Brian leads the IT, PMO and Procurement functions. With a strong foundation in technology, a successful track record in leading cross functional and multi-disciplinary project management teams, and in-depth experience in purchasing and materials management, Brian is passionate about delivering to and exceeding client expectations through critical thinking, analysis and effective communication. He brings more than 20 years experience in various industries including corporate law, pharmaceuticals, biopharmaceuticals and big data market research.

Brian completed his BSc degree in Computer Science from the University of Toronto and certified as a Project Management trainer with Kepner Tregoe.

Lisa Cline

Lisa Cline

Director, Human Resources​

As the Director of Human Resources (HR), Lisa leads this function at Dalriada. Lisa is recognized as a pragmatic partner, team builder and innovator who brings balance and clarity to HR policies, practices, and procedures.

With more than 25 years in a management capacity, Lisa is known for designing and developing programs, performance improvement measures and policies that help organizations build highly engaged workplaces, boost their bottom line, and defuse workplace issues before they escalate.

She began her HR career at GlaxoSmithKline advancing through increasingly responsible positions and supporting practically every division within the company. Lisa has also operated her own HR consultancy. Since joining Dalriada in 2020, Lisa has established an efficient and engaging HR infrastructure that delivers sustainable organizational and cultural success.

Lisa attained her Certified Human Resources Leader designation, (CHRL) from the University of Toronto.

Harpreet Kaur

Harpreet Kaur, PhD

Director Chemistry & ADME

As Director of R&D Operations, Harpreet leads Dalriada’s Chemistry and ADME functions. Passionate about building highly effective, result-oriented teams, Harpreet is known for her strong rapport with clients and inter-disciplinary colleagues.

Harpreet brings more than 20 years R&D experience in both academic and industry settings. Beginning her career at Dalton Pharma Services as a medicinal chemist, Harpreet has progressed into roles such as chemistry team leader, chemistry manager and associate director for R&D operations. Harpreet brings a broad range of drug development experience in preclinical, clinical, and commercial stages for more than 10 pre-clinical candidates and 2 commercial products. Her experience also includes contract research, process development and analytical method development and validation. She has served as SME for process development and analytical method development during FDA and Health Canada audits.

Harpreet completed her BSc degree in Biological Sciences, MSc and PhD degree in Organic Chemistry from Kurukshetra University, India.

Mohammad Eram

Mohammad Eram, PhD

Director Biology & Biophysics

Mohammad attained his PhD in Biochemistry and Enzymology at the University of Waterloo (Canada) and holds MSc degree in Medical Microbiology and a BSc degree in Cell and Molecular Biology. As the Director of Biology Department at Dalriada, he oversees the work of the cell biology, biochemistry and biophysics and proteomics teams.

Prior to joining Dalriada, Mohammad worked on early stage hit discovery projects at the Structural Genomics Consortium in Toronto, including projects in collaboration with Bayer, Takeda, Eli Lilly, and Merck. His work at SGC focused on biochemical and biophysical methods with applications to high-throughput and fragment-based drug discovery.

With over 17 years in biochemical/biophysical assays and small molecule R&D, Mohammad was involved in programs spanning small molecule inhibitor modalities including allosteric inhibitors, tight binders, targeted covalent therapeutics, and protein degraders. These programs covered a diverse range of protein targets including transcription factors, epigenetic modulators, oxidoreductases, dehydrogenases, kinases, methyl- and acetyltransferases, deacetylases, demethylases, PPI, GPCRs, and transcription regulators.

Jeff O’Meara

Jeff O’Meara, MSc

VP Drug Discovery

As Vice President, Drug Discovery at Dalriada, Jeff is responsible for overseeing all drug discovery activities from target identification to pre-clinical development. Jeff has nearly 30 years of drug discovery experience in hit ID, hit to lead, lead optimization and candidate nomination in projects targeting kinases, protein-protein interactions, protein degraders, covalent inhibitors, proteases and GPCRs in the areas of anti-infectives, oncology, immunomodulation, pain and CNS therapeutics. Prior to Dalriada, Jeff was Head of Research at M4K Pharma where he led a successful multinational open science lead optimization drug discovery project targeting DIPG, a rare childhood cancer.

Previously, Jeff spent 8 years as an integral part of the Ontario Institute for Cancer Research’s Drug Discovery team where he drove hit to lead and lead optimization projects of which two were eventually partnered with pharma in deals totaling > $2B. Jeff also trained for 17 years as a medicinal chemist and project team leader at Boehringer Ingelheim Canada Ltd. where he helped discover several novel antivirals that progressed to clinical trials. He has published more than 50 papers and patents in the fields of medicinal chemistry and drug discovery and in 2010 was the recipient of the American Chemical Society’s TAOC award.

Jeff has an M.Sc. in organic chemistry from University of Ottawa.

Tom Coulter

Tom Coulter, PhD

Head, Drug Discovery Programs and Partnerships

Tom is part of the R&D leadership team, overseeing partnership activities, drug discovery program planning and execution, as well as lifecycle management for current and prospective partners.

Over the past three decades, Tom has held senior roles in European pharma and biotech, including almost 20 years in contract research with Evotec as Senior Vice President, Drug Discovery, and more recently growing and leading Selvita’s integrated drug discovery portfolio.

Tom’s background is in medicinal chemistry, and he has extensive experience in the discovery and delivery of new small molecule and biologic agents targeting enzymes, GPCRs and other cell membrane targets including ion channels and SNARE proteins. He has managed multiple drug discovery programs covering the hit identification, hit to lead, and lead optimization stages of drug discovery, including 15 projects resulting in nomination of preclinical development candidates in the fields of cancer, inflammation, endocrine disease and antivirals. Tom has also contributed to the identification of multiple investigational new drugs. In recent years Tom has driven the identification of commercial opportunities as well as the creation and execution of sophisticated integrated discovery collaborations for clients.

Tom has a BSc (Hons) degree in chemistry from the Queen’s University of Belfast and a PhD in organic chemistry from the University of Leeds under Professor Ron Grigg. After completing his PhD, he joined Jim Thomas’ group at the University of Manchester before starting his industrial career at Organon.

Rav Kumar

Rav Kumar, PhD

Chief Strategy Officer

Dr. Rav Kumar is Chief Strategy Officer at Dalriada. He spent 25 years with GlaxoSmithKline (GSK) in the UK, France and Canada at vice-president level leading pharmaceutical R&D and business development. Key areas of expertise include formulation development, regulatory submissions, manufacturing and GMP audits. He has been involved with development of numerous medicines and vaccines plus many successful business change initiatives.

Most recently, he was Managing Director for Apotex in India (Bangalore and Mumbai), leading over 2,000 professionals in Pharmaceutical R&D, Manufacturing, Quality, Regulatory Affairs & Commercial Services.

Dr. Kumar is passionate about growing Canadian Life Sciences and has been involved with many industry-academic-government collaborations for which he was recognized with the Award for Leadership in in Canadian Pharmaceutical Sciences. He conceived the $150M spinout of GSK’s vaccines R&D to create the Neomed Vaccines and Biologics Centre of Excellence in Montreal. Other contributions include the CIHR Steering Committee for Patient Oriented Research, the Board of CQDM Research Consortium in Quebec and President of the Canadian Society for Pharmaceutical Sciences.

Dr. Kumar also serves as Director of The Centre for Medicinal Chemistry and an Assistant Professor at University of Toronto. He has a Pharmacy Degree and completed a PhD in Novel Drug Delivery at University of Bath in the UK.

Charlie Younger

Charlie Younger, PhD

Chief Operating Officer

Charlie joined Dalriada in 2020 as Chief Operating Officer, bringing over 25 years of pharma/biopharma experience. Charlie has a proven track record of leading organizations through rapid growth and transformations.

Charlie started his career as an Analytical Scientist at Glaxo and has taken on progressive leadership roles in pharma/biopharma. Charlie has worked with leading private and public pharma/biopharma organizations including leadership roles at CROs such as Patheon and Therapure Biopharma. He has also served as COO in both public and private organizations.

Driven by a personal passion to grow R&D in Canada, he has been a contributing member on multiple SR&ED tasks forces and executive roles in training organizations.

More recently, Charlie runs his own professional services business since 2016, helping companies grow and/or streamline operations for start-ups through to $B+ multinationals. He completed an HBSc in Chemistry at Western University (Canada) and a PhD in Organic Chemistry at McMaster University (Canada).

Patrick Gunning

Patrick Gunning, PhD

Co-founder & CSO

Patrick is a Professor of Chemistry at the University of Toronto, Canada Research Chair in Medicinal Chemistry, and Founder and Chief Scientific Director of the Centre for Medicinal Chemistry (UofT). Patrick obtained his PhD at the University of Glasgow in 2005 under the supervision of Profs. Robert Peacock and Andrew C. Benniston, and conducted post-doctoral studies at Yale University with Prof Andrew Hamilton.

Patrick’s research has focused on developing inhibitors of numerous protein classes, including transcription factors, kinases, and epigenetic targets, using novel covalent therapeutics and monovalent protein degraders. Patrick has published ~120 research papers, is a Fellow of the Royal Society of Chemistry, won 20 research awards including Canada’s Top 40 under 40, the 2010 Boehringer Ingelheim Young Investigator Award, the 2012 RSC MedChemComm Emerging Investigator Lectureship by the Royal Society for Chemistry, Rose Winer Levin Lectureship at the Dana-Farber Cancer Institute (2015), and the 2016 Canadian Society for Chemistry’s Bernard Belleau award.

Patrick, the co-founder and CSO of Dalriada Drug Discovery, has founded three other biotech companies with over $34M in funding, including Janpix Inc, now a Centessa Pharmaceuticals’ company, Dunad Therapeutics, and Dalriada Therapeutics.

Diana Kraskouskaya

Diana Kraskouskaya, PhD

Co-founder & CEO

Diana completed Honors BSc Degree in Molecular Biology and PhD in Medicinal Chemistry from the University of Toronto, and is a co-founder of two other biotechs, which have raised > $10 M in VC funding.

During her time in academia and biotech, Diana worked on diverse small molecule programs across protein-protein interactions, epigenetics, GPCRs, covalent inhibitors, and is an inventor on several patents.

As a co-founder and Chief Executive Officer of Dalriada, Diana brings to Dalriada years of leadership and hands-on cross-disciplinary biotech and drug discovery experience spanning areas of company building, scientific & IP program strategy, and operations. ​

Following completion of her PhD, Diana took appointment as a research manager of the Centre for Medicinal Chemistry, where she was involved in multiple drug discovery programs and provided oversight over the build-out of the >$100 M integrated drug discovery infrastructure at the University of Toronto. Diana co-founded and led two other biotechs, Dunad Therapeutics and Dalriada Therapeutics. In this process she recognized the shortcomings of the existing options for outsourcing innovative science, which led to the creation of Dalriada Drug Discovery’s Turn-Key™ Model. With this new model and under Diana’s leadership the company has grown to over 60 people within 3 years. ​

Diana is the recipient of several entrepreneurship awards, including RBC Prize for Innovation & Entrepreneurship and the 2018 MNP Future Leaders awards.

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