The Pfizer CFTR potentiator, CP-628006 , enhances CFTR function in cystic fibrosis patient-derived airwell cells with a distinct mechanism of action from existing potentiators such as ivacaftor. It has a unique chemical structure, and in contrast to other potentiators does not seem to inhibit the channel at high concentrations of drug and [...]

The Janssen pan-genotype, pan-serotype dengue virus inhibitor, JNJ-A07 , demonstrates broad activity against a panel of 21 clinical isolates and has a high barrier to resistance. It blocks the interaction between the non-enzymatic NS4B protein and NS3, preventing them from forming an NS3-NS4B complex which is essential for replication (though [...]

The Bayer P2X3 purinoreceptor antagonist, eliapixant (BAY1817080), is intended to treat various disorders associated with hypersensitive nerve fibers, including endometriosis. The hypothesis is that P2X3 receptor antagonism can inhibit cycles of pain causing neurogenic inflammation, causing pain, etc. modifying the underlying disease in [...]

The Turning Point Therapeutics oral, brain-penetrant ALK/ROS1/TRK kinase inhibitor, repotrectinib (TPX-0005), is a macrocyclic molecule with a small size intended to limit adverse interactions with resistance mutation hotspots near kinase active sites. TRK fusion proteins are driver mutations in certain cancers (which respond well to [...]

This month’s cover molecule, BMS-986278 , is an LPA 1 antagonist and oral (up to 125 mg BID) Ph. II clinical candidate for idiopathic pulmonary fibrosis (IPF) (NCT04308681). Reviewer and nominator Christian Kuttruff says: “While there are two approved molecules for the treatment of IPF (pirfenidone from Roche and nintedanib from BI), there is [...]

The Cytokinetics next-generation myosin inhibitor, aficamten , is a phase II candidate for genetic hypertrophic cardiomyopathies, and is orally dosed between 5-30 mg QD. It follows BMS’s mavacamten ( acquired from Myokardia in a $13.1B deal), whose NDA is under review by the FDA. This class of molecules is intended to address hypertrophic [...]

The bifunctional degrader, SJ995973 , was nominated by Joachim Rudolph . “Instead of the thalidomide-based cereblon binder present in the established BET degrader tool dBET1, SJ995973 uses a novel cereblon binder containing a simple phenyl ring instead of the hydrolytically labile phthalimide group. Not only is SJ995973 an extremely potent [...]

The Carna Biosciences CDC7 kinase inhibitor, AS-0141 , is a clinical candidate for cancer with a structure that contains a hydrazine, furenone, and ester, all rare functional groups for an oral molecule. The molecule has a long residence time on the kinase, and despite a short half-life in mouse, extended target engagement is observed >24 h [...]

The BMS TGFβR inhibitor prodrug, “ compound 10 ,” demonstrates antitumor efficacy comparable to the parent compound ( BMS-986260 ) in a syngeneic model with once-weekly dosing, while reducing the systemic exposure of BMS-986260. Reducing the systemic exposure of a TGFβR inhibitor is important due to previously observed mechanism-based cardiac [...]

The Sanofi glucosylceramide synthase (GCS) inhibitor, venglustat , is an oral, brain-penetrant clinical candidate for GBA -mutant Parkinson’s disease and other diseases where GBA -mutations are relevant. Though the molecule did not demonstrate efficacy within one year in early GBA -PD patients and was discontinued in this indication [...]

The Mirum Pharmaceuticals IBAT bile acid transporter inhibitor, maralixibat , has a long history, having been first patented by scientists at Searle in 1994 and published by the time Searle became part of Pharmacia in 2005 . It was finally approved in Sep. 2021 for treatment of cholestatic pruritis in patients with Alagille Syndrome, and is [...]

The Merck bicyclic macrocyclic peptide PCSK9 inhibitor, “ compound 44 ,” is a highly potent (Ki = 0.00239 nM) and orally bioavailable (cyno %F = 2.9, t1/2 = 10 h) agent against a notoriously difficult target for small molecules, demonstrating target engagement comparable to approved PCSK9 antibodies. The discovery of this molecule is an [...]

The Janssen non-ATP competitive HPK1 inhibitor, “ compound 1 ,” was identified from a screening cascade specifically looking for allosteric inhibitors, which may provide a selectivity advantage over ATP-competitive starting points. Reviewer Adi Murthy says, “ Specificity may prove challenging for HPK active site inhibitors since it belongs to [...]

The December edition of Small Molecules of the Month includes a Ph. III candidate identified from machine-learning-assisted in vivo phenotypic screening, Mirati’s KRAS G12D inhibitor, and several kinase inhibitors outside of oncology. Thanks to reviewers Joachim Rudolph, Naomi Rajapaksa, Julien Lefranc, Christian Kuttruff, Christian Gampe, Jake Schwarz, Yoana Dimitrova, Anthony Vaganos, and Kim Huard for their nominations and key insights this month. Premium subscribers can read details behind each molecule and download the slide deck. Sign up for the free e-mail newsletter to get a preview ea...

The FORUM Pharmaceuticals CNS-penetrant gamma secretase inhibitor and preclinical candidate, FRM-024 , is an advanced example of the use of an oxadiazine as an amide isostere . While amide isosteres are frequently proposed, it is often difficult to implement them beyond basic heterocyclic replacements. A benzofuran structural alert was [...]

The Lycera ROR gamma agonist, cintirorgon ( LYC-55716 ), is a first-in-class phase 1b clinical candidate for cancer immunotherapy (in combination with pembrolizumab in NSCLC). ROR gamma antagonists have been extensively pursued and studied for autoimmune conditions, but ROR gamma agonists have also been recently pursued for “pro-inflammatory” [...]

The Shionogi P2X3 ligand-gated ion channel antagonist, sivopixant ( S-600918 ), is an oral Ph. II candidate for refractory chronic cough, which recently completed a its Ph. IIb study, overcoming the projected high dose requirement of a prior preclinical candidate. The molecule has a very polar core structure with both a dioxotriazine and [...]

The Janssen PRMT5 inhibitor, onametostat (JNJ-64619178) is a selective, orally active and pseudo-irreversible protein arginine methyltransferase 5 (PRMT5) inhibitor with high selectivity and potency (subnanomolar range, PRMT5-MEP-50 IC50=0.14 nM) under various conditions. While JNJ-64619178 binds non-covalently in the PRMT5 SAM and [...]