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Small Molecule Highlights #01 – November 2022

Dalriada Small Molecule Highlights 01 - cover image

Introducing Dalriada’s Small Molecule Highlights blog series

This blog provides a snapshot of interesting and relevant small molecules recently published in prominent drug discovery journals. It was created to highlight progress in target-oriented drug discovery and new potential therapeutic opportunities. As a focused small molecule discovery services company, we are constantly evaluating new findings and trends and want to share our insights with the broader community.

In today’s post, we highlight nine small molecules disclosed in October 2022. These encompass a diverse set of targets, binding mechanisms and potential therapeutic indications such as cancer, osteoarthritis, rheumatoid arthritis, and malaria.

Dalriada Small Molecule Highlights 01 - one pager
Small Molecule Highlights #01 – November 2022

SPAA-52

Dalriada Small Molecule Highlights 01 - SPAA-52
SPAA-52

SPAA-52: Active-site directed inhibitor of low-molecular weight protein tyrosine phosphatase (LMW-PTP), with high potency, selectivity (Ki = 1.2 nM, FS >8000x vs. 24 PTPs), various drug-like properties, and moderate murine oral bioavailability (Fmouse = 23-50%).

Reference: https://doi.org/10.1021/acs.jmedchem.2c01143

Compound M16

Dalriada Small Molecule Highlights 01 - Compound M16
Compound M16

Compound M16: Diphenylpyrimidine-diamine inhibitor of Axl receptor tyrosine kinase (RTK), with high potency (IC50­ = 5 nM), and broad cytotoxicity (CC­50 <150 nM) in select cells within a panel of 42 cancer lines (e.g. MV4-11, RS4;11, SU-DHL-4, Hep 3B2.1-7).

Reference: https://doi.org/10.1039/D2MD00153E

Compound 43

Dalriada Small Molecule Highlights 01 - Compound 43
Compound 43

Compound 43: Using a 200K HTS strategy towards a novel bromodomain and external terminal domain (BET) inhibitor (BD1 IC50 = 0.24 uM). Resolution of fragment co-crystal with BRD4-BD1 (PDB 7W3D) highlighting novel interactions relative to thienotriazolodiazepine BETi JQ1(+).

Reference: https://doi.org/10.1016/j.bmc.2022.116967

UCB7362

Dalriada Small Molecule Highlights 01 - UCB7362
UCB7362

UCB7362: Inhibitor of aspartyl protease Plasmepsin X (PMX) (involved in malarial parasite egression/ erythrocyte invasion/functional merozoite development) with demonstrated potency in biochemical (PMX IC50 = 7 nM,), cellular models (Pf 3D7 IC50 = 10 nM), and in vivo murine models (50 mg/kg).

Reference: https://doi.org/10.1021/acs.jmedchem.2c01336

Compound 30

Dalriada Small Molecule Highlights 01 - Compound 30
Compound 30

Compound 30: N-(methyl-d3)pyridazine-3-carboxamide inhibitor of Tyrosine kinase 2 (TYK2), involved in IL-12, IL-23, and IFN signalling, which are largely implicated in auto-immune disorders. IFNa IC50 = 1.90 nM, with efficacy in IL-23 acanthosis/anti-CD40-induced colitis models.

Reference: https://doi.org/10.1021/acsmedchemlett.2c00334

Compound 23

Dalriada Small Molecule Highlights 01 - Compound 23
Compound 23

Compound 23: Starting from pre-clinical analog MK-1256 towards a novel lead inhibitor of cysteine protease Cathepsin K (Cat K), with therapeutic implications in osteoarthritic (OA) disease. In vitro Cat K IC50 = 0.5 nM, with selectivity against Cat L, B, S, F, V, and extensive characterization of in vivo PK.

Reference: https://doi.org/10.1016/j.bmcl.2022.128927

Compound 8O

Dalriada Small Molecule Highlights 01 - Compound 8O
Compound 8O

Compound 8O: Oral, potent, and selective pyrrolo[2,3-d]pyrimidine Janus kinase 1 (JAK1) inhibitor as a prospective therapeutic strategy against rheumatoid arthritis (RA). Biochemical JAK1/JAK2 IC50 = 0.3/3.6 nM, with improved in vivo efficacy in a murine CIA model relative to Tofacitinib.

Reference: https://doi.org/10.1016/j.bmcl.2022.128905

Compound 17

Dalriada Small Molecule Highlights 01 - Compound 17
Compound 17

Compound 17: Protein-protein interaction (PPI) inhibitor of the Protein arginine methyl transferase 5 (PRMT5):methylosome protein 50 (MEP50) interface. Identified via ZINC virtual screen (30 million) towards a powerful lead with cytotoxicity (IC50 < 500 nM), cell target engagement and a novel MOA.

Reference: https://doi.org/10.1021/acs.jmedchem.2c01000

Compound 2F

Dalriada Small Molecule Highlights 01 - Compound 2F
Compound 2F

Compound 2F: Inhibitor of Farnesyl transferase (FTase), disrupting Ras signalling in neoformans as a therapeutic strategy towards novel anti-fungals. Resolution of co-crystal (PDB 7T0A), and Minimum inhibitory concentrations (MICs) of fungal growth 4-8x better rel. to Fluconazole (Diflucan).

Reference: https://doi.org/10.1021/acs.jmedchem.2c00902

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

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Lisa Cline

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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.

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Eric Chow

Director, Finance

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Over his career, Eric has worked internationally in the US and the UK. Eric completed his BComm Finance and BA Economics from the University of Calgary and is a CPA, CMA.

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Kamran Syed

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Harpreet Kaur, PhD

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Chief Operating Officer

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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.

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Diana Kraskouskaya, PhD

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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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