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: 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%).
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).
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(+).
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).
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.
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.
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.
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.
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).