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Small Molecule Highlights #20 – February 2024

Small Molecule Highlights #20 – February 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 the SIK 1/2/3, RORγ, PAPD 5/7, KRAS (G12D), and SOS1. Enjoy!

GLPG3312

GLPG3312
GLPG3312

GLPG3312: The team at Galapagos took aim at developing a pan-SIK (SIK1/2/3) inhibitor to complement its pipeline of small molecules targeting inflammatory diseases (Filgotinib, a.k.a. Jyseleca, targeting JAK1 has been approved for the treatment of rheumatoid arthritis and ulcerative colitis). After a high throughput screen of their internal kinase focused library (42,000 compounds), the medicinal chemistry team discovered a potent SIK3 compound as a starting point. Fortuitously, this initial compound contained a wealth of handles for modification, facilitating optimization of the scaffold. Multiple rounds of SAR, highlighted by the incorporation of amido-cyclopropane and difluoromethoxy substituents to increase potency and selectivity for SIK1/2/3, followed by lead optimization/evaluation where required to arrive at clinical candidate GLPG3312. A close congener of the compound was co-crystallized with SIK3, providing valuable insights into the selection of the lead compound and potentially informing future projects (more below). The co-crystal (PDB ID: 8OKU; atomic coordinates were unavailable at the time of writing) is the first reported x-ray structure of a SIK protein family member. In biochemical assays (ADP-Glo), GLP3312 exhibited potent inhibition of all three SIKs (2.0/0.7/0.6 nM for SIK1/SIK2/SIK3, respectively) and good selectivity (DDR1, LIMK1, MAP3K20, and RIPK2 were the only kinases to show > 80% inhibition @ 1 uM in the Eurofins Kinome Panel). Pharmacokinetic characterization of the compound revealed low mouse liver microsome and hepatocyte clearance (4.76 L/h/kg and <1.75 4.76 L/h/kg, respectively) and respectable oral bioavailability in mouse, rat, and dog (F = 60/41.4/45.5% in mouse/rat/dog, respectively). In vivo efficacy was assessed in an LPS challenge model in Balb/c mice where GLPG3312 was shown to have a dose-dependent effect on serum TNFα and IL-10 concentrations (77% decrease in TNFα and 3.1-fold increase in IL-10 was observed at 3 mg/kg). The authors indicated that GLPG3312 was progressed to a phase 1 clinical trial (NCT03800472) looking at two separate formulations/exposure regimens in healthy individuals. Also teased was GLPG3970; a novel selective SIK2/SIK3 inhibitor candidate.

Reference: https://doi.org/10.1021/acs.jmedchem.3c01428

JTE-151

JTE-151
JTE-151

JTE-151:  There is increasing evidence supporting the role of IL-17 and Th17 cells in chronic inflammation, with several pharmaceutical companies investing in modalities targeting this pathway. Biologics targeting IL-17 have garnered a bulk of the attention/success, however, inherent pharmacokinetic limitations have shifted attention onto retinoic acid receptor-related orphan receptor gamma (RORγ) as a promising target for small molecule intervention. The challenge, nuclear receptors, such as RORγ, are heavily hydrophobic leading to selectivity and solubility issues for designed ligands/inhibitors/agonists. The authors took a pragmatic approach towards the development of JTE-151 by incorporating “drug-likeness” as a major design consideration and candidate selection criteria. As such, non-typical chemotypes, rarely seen in nuclear receptor development programs, were considered, and SAR decisions were heavily influenced by ligand efficiency (LE) and sp3 carbon content. Every appendage, including the iso-oxazole core, was surveyed, and optimized to arrive at JTE-151. Interestingly, the co-crystal of the compound with RORγ (PDB: 8X7E) shows a unique binding orientation, with the hydrophobic portion of the molecule pulled back in an almost U-shape conformation and the carboxylic acid group (positioned at the bottom of the U) projecting outside of the pocket towards solvent. Compound efficacy was first assessed in a cellular luciferase activity assay (CHO-K1 cells) were JTE-151 exhibited low nanomolar inhibition (EC50 = 13 nM) of RORγ. Specificity was demonstrated in a panel of closely related and often hit nuclear receptors (100-fold selectivity was observed). In pharmacokinetic studies, JTE-151 displayed low clearance (CL = 0.11 L/h/kg) in rats and good overall bioavailability in mouse and dog (F = 98 and 64% in mouse and dog, respectively). In vivo, the compound was shown to dose-dependently decrease the severity of paralysis in a mouse model of experimental autoimmune encephalomyelitis (EAE). In toxicology studies, an initially observed hERG liability (patch-clamp assay) was ruled out as insignificant in further cardiac telemetry studies in conscious dog (no QTcF elongation at doses of 100 mg/kg p.o. BID). Measures of genotoxicity CHL cells and a GLP-complaint toxicity study in rats and dog did not reveal any development limiting toxicity. Recently, JTE-151 was assessed in clinical trials with results from a phase I study being reported shortly. The authors offered a small preview of the results by disclosing dose tolerance results. JTE-151 was well tolerated in healthy individuals (30 – 1600 mg doses) with no observable plateauing of plasma concentration within the dose range tested. Also, no severe adverse effect/events were observed at the highest dose of 1600 mg/kg. It will be interesting to see how far JTE-151 progresses.     

Reference: https://doi.org/10.1021/acs.jmedchem.3c01933

AB-452

AB-452
AB-452

AB-452:  What a difference an N makes. The medicinal chemistry team at Arbutus Biopharma were looking to develop a small molecule therapeutic to reduce plasma concentrations of Hepatitis B soluble antigen (HBsAg) to mitigate T-cell exhaustion in HBV infected individuals. Using RG7834 (Roche) as a starting point, the team considered a simple expansion of the central 6-membered ring to a 7-membered oxazepine. While a concise SAR of catechol appended substituents led to two potential candidates, undesirable PK profiles in rat and a substantial hERG liability halted further development. In parallel, the team explored the incorporation/replacement of the terminal catechol ring with a variety of heteroaromatics. An SAR covering pyridines (various regioisomers), pyridones, thiophenes, and thiazoles led the team to a very minor modification of the parent scaffold, a substitution of an aromatic carbon with nitrogen. Introduction of the pyridine had no effect on the potency or cytotoxicity of AB-452 compared to RG7834 (EC50 = 1.2 nM and CC50 > 50 μM, respectively). A marked difference was observed in PK and toxicity studies where AB-452 was shown to have 2-fold greater oral exposure (rat and dog) compared to RG7834 and no effect on cardiac telemetry measurement (ECG) at 10 μM concentration. Given the improved PK and safety profile of AB-452 over RG7834, efficacy in a murine in vivo model of HBV infection was assessed. In the study, a dose-dependant decrease in serum and liver HBsAg, as well as Liver HBV RNA, was observed after 7 days (3/10/30 mg/kg, p.o., once daily). The authors quickly glossed over results from a preclinical safety study where signs of peripheral neuropathy were observed after chronic dosing in rat and dog. Similar results in monkey were observed for RG7834, indicating an issue with the overall scaffold rather than the modifications inherent to AB-452.  Further optimization of the scaffold to circumvent the observed neuropathy was intimated by the authors.                

Reference: https://doi.org/10.1021/acs.jmedchem.3c01981

8o

8o
8o

8o:  The KRAS G12D mutation is the most common oncogenic variant of the protein and a prevalent escape mechanism from G12C targeted therapeutics (i.e. sotorasib and adagrasib). As the G12D mutation has an aspartic acid in place of the targeted cysteine, thus eliminating the possibility of covalent modification, the creators of adagrasib (Mirati Therapeutics) have successfully re-tooled the compound into a selective reversible inhibitor of G12D protein (MRTX1133). As MRTX1133 is currently in phase 1 clinical trials, with results yet to be reported, there is concern over rapidly acquired drug resistance, similar to what was observed with G12C inhibitors.  As such, targeted degradation is being looked at as a complementary therapeutic strategy for individuals harboring KRAS G12D. To develop a PROTAC for G12D, the authors maintained the pyridopyrimidine core and Asp 12 bicyclo amine recognition substituent of MRTX1133, however, the solvent exposed 5,5-fused bicylic amino group was replaced with a simpler prolinol substituent, similar to that of adagrasib.  Swap to the prolinol was a pragmatic design decision as it offered an easily tapped handle for application of the linker and VHL recruitment substituents and had the appropriate exit vector. The original naphthalene group was slightly modified, with an ethyl group replacing the alkyne. This might have been done to counter chemical atropism concerns, almost a certainty in such a congested scaffold.  A survey of various linkers identified n-butanol as the best substituent to form the ternary complex. Rigid heterocyclic linkers were also sampled but found to be less effective. The authors didn’t waver from their choice of VHL ligand, stating inspiration from LC-2, a G12C targeting covalent PROTAC based, to support their design.  However, with multiple players in the space, including Arvinas, Erasca, and Shanghai Pharma, their SAR choices may have been guided, in part, by chemical white space and IP strategy. The in vitro validation of 8o was comprehensive and exhaustive to say the least. To start, cooperativity measurement looking at the formation of binary (PROTAC + KRAS G12D) vs ternary (PROTAC + KRAS G12D + E3 ligase) was used to evaluate the efficiency of ternary complex formation. Cooperativity measurements were compared to cellular degradation results to deconvolute cellular uptake of compound and inform further SAR decisions. Degradation selectivity across 7 cell lines encompassing KRAS G12D, G12C, G12V, G12S, G12R, and G13D mutants, as well as a WT cell line, was demonstrated at 0.1 and 1 μM.  Proteomics experiments were conducted to probe off-target effects more completely. Of the 7510 detected proteins, only DUSP4 and KRT5/9/14 were significantly depleted. Downregulation of DUSP4 was later proven in the article to be dependant on KRAS degradation.  Efficacy in cancer relevant cell lines was assessed where 8o exhibited dose-dependent degradation of KRAS G12D in SNU-1, HPAF-II, AGS, and PANC 04.03 cells with corresponding DC50 values of 19.77, 52.96, 7.49, and 87.8 nM, respectively. Compound 8o also exerted an inhibitory effect on the ERK signaling pathway, with durable inhibition of ERK phosphorylation being observed 72 hours post washout in AsPC-1 cells. Pharmacokinetic characterization in Balb/c mice revealed good plasma exposure (AUC0–∞ = 5057 ± 546 h·ng/mL) and long serum half-life (T1/2 = 8.70 ± 2.47 h) after subcutaneous injection. This uncommon mode of delivery raises concerns about the bioavailability of the compound and its potential for oral administration. Pharmacodynamic evaluation in AsPC-1 mouse xenograft study confirmed efficacy of 8o in an in vivo setting. In the PD model, KRAS G12D was significantly depleted 24 hours post dose, with protein levels not fully recovered after 72 hours. Also, tumor growth was inhibited by a respectable 68% over a 22-day chronic dosing (50 mg/kg, QD, s.c.) study with no signs of toxicity. In the same study, MRTX1133 inhibited tumor growth by 89%, albeit, employing a different method of administration (30 mg/kg, BD, i.p.). Taken as a whole, 8o looks to be a promising lead compound in need of further PK optimization to become a potential treatment option for KRAS G12D driven pathologies.

Reference: https://doi.org/10.1021/acs.jmedchem.3c01622

Compound 4

Compound 4
Compound 4

Compound 4:  Staying with the theme of KRAS pathway modulation via PROTACs, a collaboration between Shanghai Zelgen Pharma-Tech and the East China University of Science and Technology have reported a new SOS1 targeting PROTAC. SOS1 (Son of Sevenless 1) plays a key role in the KRAS signalling pathway by facilitating nucleotide release from the inactive KRAS-GDP complex. As a therapeutic target, SOS1 inhibition/depletion has been viewed as a strategy to circumvent resistance mutations arising from drugs targeting KRAS directly. Indeed, there are multiple clinical trials looking at SOS1 inhibitors in combination with KRAS G12C therapeutics, however, no PROTACs have been evaluated in combination studies or as a monotherapy in a clinical setting. The medicinal chemistry team decided to use BI3406 (Boehringer-Ingelheim) as a starting scaffold, and quickly analyzed options for appending the E3 ligase ligand. Fortunately, the tetrahydrofuran substituent was ideally placed (solvent exposed), however, it lacked a viable attachment point for the E3 ligand. As such, the team opted to go with a methylamino cyclopropane as similar molecules have been shown to inhibit formation of the KRAS G12C/SOS1 complex. A survey of various linkers indicated that conformationally rigid and heteroatom containing substituents were not tolerated, leading the team to select a 6-carbon aliphatic chain as the ideal linker. Further SAR centered around the CRBN ligand (E3 ligase ligand) and the pendant trifluoromethyl aniline revealed little room for modification. Compound 4 exhibited low nanomolar antiproliferative properties (IC50 = 5 nM) and potent SOS1 degradation in NCI-H358 cells (DC50 = 13 nM, Dmax = 88%). Furthermore, cell proliferation was attenuated in several other cell lines expressing different KRAS mutations (GP2D(G12D), NCI-H441(G12V), and DLD-1(G13D)). Pharmacokinetic characterization of 4 revealed a long plasma half-life (T1/2 = 4.05 h) and good plasma exposure (AUC0–∞ = 4378 h·ng/mL) following intraperitoneal administration. In vivo tumor control was demonstrated in a H358 xenograft study in BALB/c mice. Compound 4 was shown to inhibit tumor growth by almost 60% (30 mg/kg, i.p., 21-days), outperforming BI3406 (30 mg/kg, p.o.) by nearly 2-fold.  Collectively, the data suggest compound 4 to be an interesting clinical development candidate.    

Reference: https://doi.org/10.1021/acs.jmedchem.3c02135

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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.

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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

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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.  

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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, 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.

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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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