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Small Molecule Highlights #10 – March 2023

The following 7 molecules have been recently reported as molecular binders of various interesting medicinal targets, including epigenetic hydrolases (e.g. HDACs), oncology-implicated kinases (e.g. BTK), anti-viral targets (e.g. HBV), anti-psychotic GPCRs (e.g. GPR52), as well as novel targets, such as RIPK1, with prospective utility against respiratory illnesses such as acute respiratory distress syndrome (ARDS). The following articles can be found in J.Med.Chem., ACS. Med. Chem. Lett., and Eur. J. Med. Chem.

Small Molecule Highlights #10 – March 2023

Compound 19h

Compound 19h
Compound 19h

Compound 19h: The following triazole-based small molecule was reported as a histone deacetylase (HDAC) inhibitor, selective for class I isoforms: HDAC1, HDAC2, HDAC3. Inhibitor design involved a structurally focused interrogation of various surface cap groups. In biochemical assays, this compound found an IC50 of 47 nM, 125 nM, and 450 nM against HDAC1, HDAC2, and HDAC3, respectively. While an IC50 of > 10 µM was reported for the remaining deacetylase isoforms (HDAC4-HDAC11). Broad anti-proliferative activity was found across various cell lines, including MC38, HCT116, A549, PC-9, ES-2, and DoHH2. Mechanistic studies revealed this molecule results in cell cycle arrest, and FACS analysis demonstrated the induction of apoptosis. In vivo efficacy was observed in both MC38 and HCT116 xenograft models with TGI values of >80% in both cases.

Reference: https://doi.org/10.1021/acs.jmedchem.2c01985

BGB-8035

BGB-8035
BGB-8035

BGB-8035: This molecule was recently reported by BeiGene as a covalent inhibitor of Bruton’s Tyrosine Kinase (BTK). Inhibitor design was focused on several improvements on the well established covalent BTK inhibitor Zanubrutinib (Brukinsa®), with respect to selectivity, as well as targeting the kinase DFG-out conformation. The MOA follows a standard covalent 1,4-conjugate addition between the canonical acrylamide electrophile, and BTK Cys481. In vitro, an IC50 of 1.1 nM was found against BTK, with values of 621 nM, and 99 nM against EGFR and TEC proteins. In a kinome screen, common off-targets included TXK, NLK, and BMX. In a cellular environment, against pBTK (p223), an IC50 of 14 nM was reported, while pTEC returned a value of 223 nM, and pEGFR found an IC50 of > 10 µM. In vivo efficacy was also demonstrated in both a REC-1 xenograft model (TGI = 79%), as well as a Collagen-induced arthritis (CIA) rat model.

Reference: https://doi.org/10.1021/acs.jmedchem.2c01938

RG7907

RG7907
RG7907

RG7907: This structurally elaborate small molecule was recently reported by CICoR (Roche), as a Hepatitis B Virus (HBV) core protein allosteric modulator, with utility as an anti-viral therapeutic. The structural core involves a hetero-aryldihydropyrimidine, which stems from previous known HBV ligands, such as HAP_R01. In HegP.2.2.15 cells, against HBV DNA, an EC50 of 6 nM was found, while in HepDE19 cells, limited cytotoxicity was observed with a CC50 of > 100 µM. A co-crystal structure was determined against Cp149 Y132A (PDB 8I71), which highlights interactions with Trp125, and a hydrogen-bond network with a nearby H2O molecule. Extensive in vivo pharmacokinetic characterization was performed, in many models, including rat, monkey and minipig (with oral bioavailability observed across all 3 cohorts). In vivo efficacy was also observed in an adeno-associated virus-HBV mouse model (at 20 mg/kg, q.d.).

Reference: https://doi.org/10.1021/acs.jmedchem.3c00173

HTL0041178

HTL0041178
HTL0041178

HTL0041178: The following molecule with a lactam-pyrrolo-core out of Sosei Heptares has been reported as a GPR52 agonist, identified via rational fragment-based drug discovery (FBDD). GPR42 is an orphan G-αs G protein-coupled receptor (GPCR) with critical roles in both D1, D2 signaling. Calculated physicochemical properties returned values of cLogP = 3.1, tPSA = 60 Å2 , GPR52 pEC50 = 7.5 and Chrom. LLE = 3.6. Molecular docking studies demonstrated strong superposition with control compound c17. In vivo PK analysis (3 mg/kg, p.o.) revealed a CMax of 486 ng/mL, and an oral bioavailability (F %) of 95%. Efficacy was also established in a d-amphetamine-induced hyperactivity/locomotion model in rats.

Reference: https://doi.org/10.1021/acsmedchemlett.3c00052

Compound 11

Compound 11
Compound 11

Compound 11: This arylpiperazine-based small molecule has been reported as a multi-target binder of aminergic GPCRs, with prospective utility as an anti-psychotic therapy. This polypharmacology involves antagonism against D2/5-HT2A, and agonism against the 5-HT1A receptor. Using a competitive radio-ligand binding assay, Ki values of 596 nM, 56.6 nM, and 66.7 nM were reported against D2, 5-HT1A, and 5-HT2A, respectively. Off-targets such as 5-HT2C, and H1 returned Ki values of 552 nM, and 1141 nM. Agonism against 5-HT1a (cAMP signalling) observed an EC50 of 160 nM, while 5-HT2A antagonism (IP) found a Kb of 96.4 nM.

Reference: https://doi.org/10.1016/j.ejmech.2023.115285

Compound C16

Compound C16
Compound C16

Compound C16: This structurally complex α-aminoketone 4-ring system has been reported as a dual inhibitor of p53-MDM2, and MDMX. The p53-MDM2/MDMX interactions importantly regulate the transcriptional response of p53 (also known as guardian of the genome). Through rational structural optimizations, a Ki value of 0.23 µM was reported against MDM2, and 2.54 µM against MDMX. As for anti-proliferative activity, an IC50 of 0.68 µM was found in HCT116 cells, and 0.54 µM against SH-SY5Y cells. Extensive MM/GBSA calculations were performed to study/identify binding hot-spot residues of MDM2/MDMX. In addition, the inhibition of HCT116 migration and invasion was observed, along with the re-activation of p53 activity.

Reference: https://doi.org/10.1016/j.ejmech.2023.115282

SZM-1209

SZM-1209
SZM-1209

SZM-1209: This benzothiazole molecule has been recently revealed as an inhibitor of Receptor-Interacting Protein Kinase 1 (RIPK1). Interestingly, RIPK1 has been validated as one of the few targets for Acute lung injury/acute respiratory distress syndrome (ALI/ARDS). Inhibitor design utilized a ligand-based scaffold hopping strategy, based on previously established necroptosis inhibitors. Anti-necroptosis, an EC50 of 22 nM was found, while with respect to cytotoxicity, a CC50 of > 100 µM was reported (representing an improvement relative to standard analog TAK-632). Against RIPK1, a Kd value of 85 nM was found, while against RIPK3, a Kd of > 10 µM was observed. This signifies a >100x fold-selectivity for RIPK1. In vivo anti-inflammatory effects were also observed in an NNK-induced ALI model.

Reference: https://doi.org/10.1021/acs.jmedchem.3c00197

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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

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Harpreet Kaur, PhD

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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.

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Jeff O’Meara, MSc

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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.

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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.

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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

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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.

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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.

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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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