Small Molecule Highlights #01 - November 2022


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.




SPAA-52

- SPAA-52: Low-molecular weight protein tyrosine phosphatase (LMW-PTP) active-site directed inhibitor, displaying high potency (Ki = 1.2 nM) and selectivity (FS >8000x) against 24 PTPs). Murine oral bioavailability of % Fmouse= 23-50%, with limited CYPi (10 μM,) and apparent cellular permeability of Papp > 0.2 nm/s.


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



Compound M16

- Compound M16: Axl receptor tyrosine kinase (RTK) diphenylpyrimidine-diamine inhibitor, with high potency (IC50­ = 5 nM), and 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

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


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



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

- 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

- Compound 23: Starting from pre-clinical analog MK-1256 towards a novel 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

- 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

- 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 an inhibitor with cytotoxicity (IC50 < 500 nM), cellular target engagement and a novel MOA.


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



Compound 2F

- Compound 2F: Inhibitor of Farnesyl transferase (FTase), disrupting Ras signalling in C. 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