The Takeda cholesterol 24-hydroxylase inhibitor, soticlestat (TAK-935, previously OV935) is a potent, highly selective, first-in-class inhibitor of the brain-specific enzyme cholesterol 24-hydroxylase (CH24H). Cholesterol 24-hydroxylase converts cholesterol to 24S-hydroxycholesterol, which acts as a positive allosteric modulator of [...]

The BMS spirocyclobutene-containing FXR agonist, BMS-986318 , appears to have been intended as a clinical candidate, but was withdrawn from a planned Ph. I study. The molecule exhibits potent in vitro and in vivo activation of FXR (FXR Gal4 reporter EC50 = 53 nM, SRC-1 recruitment assay EC50 = 350 nM) and demonstrates efficacy in the mouse [...]

The Takeda MAGL inhibitor, “compound 4f” , was selected by reviewer Joachim Rudolph . “MAGL (monoacylglycerol lipase) is implicated in neuroinflammation, and inhibitors of this enzyme are of interest as therapeutics in neurodegenerative and other neurological diseases. Most of the advanced compounds, including the clinically evaluated [...]

The Merck CETP inhibitor backup, MK-8262 , is potential best-in-class CETP inhibitor, which was only discontinued as a backup due to the success of its predecessor, anacetrapib in Ph. III. Reviewer Kim Huard thought this CETP inhibitor was a great piece of work from Merck, and is a great example how to deal with a very lipophilic binding site [...]

The Zentalis Wee1 inhibitor, ZN-c3 , is a highly selective kinase inhibitor that is currently being evaluated in Ph. II clinical trials in adult women with recurrent or persistent uterine serous carcinoma (USC). The starting pyrazolopyrimidinone series was from the WO2013126656 patent, and while the molecule is similar to other kinase [...]

The H3 Biomedicine RNA splicing modulator, H3B-8800, targets the spliceosome SF3b complex containing either wild-type (WT) or mutant SF3B1. Splicesome inhibition can induce synthetic lethality since cancer cells bearing spliceosome mutations are more dependent on WT spliceosome function. The compound is derived from the natural product [...]

The Minoryx peroxisome proliferator-activated receptor gamma (PPARγ) agonist, leriglitazone, is one of the several metabolites of pioglitazone, a member of the thiazolidinedione (glitazone) drug class for diabetes. It is instead being developed for a rare peroxisomal neurodegenerative disease, X-linked adrenoleukodystrophy (X-ALD). It [...]

The Chiesi M3 antagonist/PDE4 inhibitor dual pharmacology molecule, compound 92a, is an inhaled compound intended for pulmonary diseases. Both M3 and PDE4 are clinically validated targets for COPD (e.g. ipratropium and roflumilast). Dual pharmacology was thought to be valuable over two independent inhibitors in part due to the potentially [...]

The University of Michigan menin-MLL inhibitor, M-1121, is a covalent protein-protein interaction inhibitor that is orally active and achieves complete tumor regression in a xenograft model (300 mpk PO QD). MLL gene fusions are drivers of leukemias via interaction with menin, and small molecule menin-MLL inhibitors have shown preliminary [...]

The Artios Pharma selective allosteric Polθ DNA polymerase inhibitor, ART558, induces synthetic lethality in BRCA-mutant cancer cells and enhances PARP inhibitor activity. Defects in the 53BP1/Shieldin complex (which cause PARPi resistance) result in sensitivity to Polθ inhibition. The molecule is orally active in a mouse xenograft model [...]

The Pfizer CDK2/4/6 inhibitor PF-60873600 is orally bioavailable with Ki values of 0.09 nM, 1.3 nM, and 0.16 nM for CDK2, CDK4, and CDK6, respectively, with lower activities against CDK1 (4.5 nM) and CDK9 (20 nM). PF-06873600 entered in Ph. I/IIa in 2018 against HR+ HER2- breast and ovarian cancers. Control of the cell cycle through [...]

The Lilly beta-site APP cleaving enzyme (BACE) inhibitor LY3202626 is an oral, low-dose, CNS-penetrant molecule which entered a Phase II of clinical trial against Alzheimer's disease in 2016. In a Ph. I study, only 9.2 mg of LY3202626 were needed to achieve 90% CSF Aβ reduction. Similar to other BACE inhibitors, development was halted due [...]

The AstraZeneca inhaled dual PI3Kγ,δ inhibitor AZD8154 is long-acting in the lung but has low systemic exposure and is selective, potentially avoiding the known side effects of systemic PI3K inhibition. The molecule is active in cells derived from asthmatic patients as well as in a rat model, and entered Ph. 2 trials (NCT04187508) but was [...]

The Gilead Toll-like receptor 7 (TLR7) agonist, vesatolimod (GS-9620), is a tolerated, low-dose oral TLR7 agonist. It is intended to induce immune cell activation to help eliminate reservoirs of HIV during antiviral therapy. It was first developed to treat chronic hepatitis B and C infection to induce a liver-targeted antiviral effect [...]

The Venatorx serine β-lactamase inhibitor VNRX-7145 is an orally bioavailable prodrug of the boronic acid-containing inhibitor VNRX-5236, and is currently in Ph. I. It demonstrates activity in vitro and in vivo covering Enterobacterales expressing key class A or D carbapenemases or class C cephalosporinases. In preclinical studies, the [...]

The Turning Point Therapeutics CNS-penetrant ALK kinase inhibitor, TPX-0131, is more potent in vitro than all 5 approved ALK inhibitors against WT-ALK and many ALK resistance mutations, including G1202R and gatekeeper mutation L1196M. This relatively small macrocycle doesnÕt rely on the solvent front region of the kinase for activity [...]

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 [...]