The Revolution Medicines selective mTORC1 complex inhibitor, RMC-4529, is a bi-steric inhibitor that has a rapamycin-derived, FKBP12-recruiting allosteric mTOR inhibitor covalently linked to an active-site (orthosteric) inhibitor of the mTOR kinase. By inhibiting both binding sites of mTOR, >30-fold selectivity for the mTORC1 complex over [...]

The Shionogi beta-lactamase inhibitor (BLI) cyclohexyl ester prodrug, compound 21, is a molecule with an interesting sulfinylamide motif on a strained bridgehead nitrogen amide core. The authors used an interesting radical decarboxylative thiolation to introduce the sulfinyl group. This potent oral BLI restores the antibacterial activity [...]

The Biogen compound BIO-32546 is a potent (IC50 = 1 nM), selective, oral, non-zinc-binding reversible autotaxin (ATX) inhibitor, and is an interesting example of a relevantly large brain-penetrant zwitterion. The molecule has a distinct structure from ATX inhibitors previously highlighted (e.g. Small Molecules of the Month May, Jul., Nov [...]

The October edition of Small Molecules of the Month includes several potential best-in-class clinical candidates including but not limited to a second-gen LPA1 antagonist from BMS, two muscle modulators from Cytokinetics, and a Janssen pan-genotype, pan-serotype Dengue virus inhibitor. There are several interesting modalities including an oral macrocyclic peptide from Merck, a tumor-specific prodrug from BMS, and a CRBN-based degrader that no-longer needs two imide motifs from St. Jude. As always, there’s plenty of interesting chemical groups – a hydrazine, furenone, pyrrole, decalin, strained...

Antibody-drug conjugates (ADCs) have gone through several waves of enthusiasm since being first tested in animal models in the 1960’s. The first clinical trials with ADCs were conducted in the 1980’s, and an ADC was first approved in 2000 (Mylotarg, see below). Mylotarg, however, was famously withdrawn from the market first, before being [...]

Recently our non-profit partner, California Life Sciences , completed nominations for the 2021 Pantheon Award for Scientific Advancement . We’re glad to see several drug hunters and drug discovery companies across the award categories, and we hope you’ll help get some industry drug hunters deserved recognition for their achievements by voting [...]

The FOLR1-targeting folate receptor-dependent PROTAC conjugate, folate-MS432 , is a MEK1/2 degrader that is targeted to FOLR1, a receptor highly expressed in many cancer cell types but less so in most normal cells. The folate moiety allows the molecule to be taken up into cells via endocytosis, where the inert molecule can be cleaved by [...]

The Merck ROMK potassium channel blocker, MK-8153 , is a backup development candidate to MK-7145, whose development as a diuretic was terminated after a Ph. Ib study due to lack of efficacy. Traditional loop diuretic drugs such as furosemide inhibit the Na-K-Cl co-transporter, but carry the risk of life-threatening urinary potassium loss [...]

The Janssen RORgt inhibitor, JNJ-61803534 , is an oral clinical candidate that was well-tolerated in humans up to 200 mg and demonstrated PD. Unfortunately, development was terminated due to findings in a rabbit embryo-fetal study where fetal development was impacted by JNJ-61803534 treatment. The JNJ team shares a lot of useful human data in [...]

The Merck LMP7 inhibitor, M3258 , is an orally available, selective, and reversible inhibitor of the immunoproteasome proteolytic subunit, LMP7. In contrast to the constitutive proteasome, the immunoproteasome is predominantly expressed in hematolymphoid cells such as in multiple myeloma cells. Pan-proteasome inhibitors (pan-PIs) such as [...]

The BMS CCR2 inhibitor, BMS-753426 , is a potent, oral follow-up molecule to prior clinical candidate, BMS-741672. A small change from a methyl and isopropyl-substituted tertiary amine to a t -butyl secondary amine led to a significant improvement in PK properties including lower clearance and higher bioavailability across species, including [...]

The Lutris-Parma topical BRAF inhibitor, LUT014 , is intended to treat rash caused by EGFR inhibitors. Rash is a significant and common side effect of EGFR inhibitor treatment leading to worse quality of life and treatment discontinuations. The rash is on-target, caused by reduced ERK signaling in healthy skin cells. Interestingly, due to [...]

The Genentech PI3Kα isoform-selective kinase inhibitor and mutant PI3Kα degrader GDC-0077 (inavolisib) selectively depletes the oncogenic mutant p110α catalytic subunit of PI3Kα in cancer cells with active receptor tyrosine kinase (RTK) signaling. The gene encoding p110α, PIK3CA, is one of the most frequently mutated oncogenes, with over 2M [...]

The Takeda CDC7 serine/threonine kinase inhibitor, simurosertib (TAK-931) , is the first orally active CDC7-selective inhibitor and recently had its Ph. I study results in solid tumors posted. The drug was dosed as a single agent in one study at 50 mg QD with 7-day rest periods on 21-day cycles, and in another study at varying levels with [...]

The Novartis mutant and WT CFTR potentiator, icenticaftor (QBW251) , is an oral Ph. II clinical candidate for chronic obstructive pulmonary disease (COPD), which is anticipated to become the 3 rd leading cause of death globally. The compound had positive proof of concept studies in both cystic fibrosis and COPD, and the advancement of a WT [...]

The Hanmi/Genentech type II RAF kinase inhibitor, belvarafenib , is a potent and selective inhibitor of RAF dimers. GNE-9815 was covered last month , which was used to validate the biology supporting clinical trials of belvarafenib. This Nature article shares first-in-human results of belvarafenib in BRAF(V600E) and RAS-mutated solid tumors [...]

The Galapagos S1PR2 antagonist GLPG2938 is a preclinical candidate intended for the treatment of idiopathic pulmonary fibrosis (IPF). Though several S1PR1 modulators have been approved, no selective S1PR2 antagonist has entered clinical development yet. The Galapagos team attempted to find a new starting point with two consecutive HTS [...]

The EpiCentRx Myc and CD47 downregulating molecule with a range of proposed mechanisms, RRx-001 , is a Ph. III clinical candidate with an eyebrow-raising chemical structure that originated from an even more eyebrow-raising starting point, trinitroazetidine. The N -nitro motif in the starting point was replaced with the (only slightly) less [...]