What is it? RMC-5552 is a potential first-in-class, bi-steric, mTOR1-selective inhibitor in Ph. I/IIb ( NCT04774952, NCT05557292) as an IV agent to treat tumors with hyperactive mTORC1 signaling. This previously highlighted molecule is a bi-steric inhibitor containing an allosteric C32-hydroxy rapamycin derivative linked to an orthosteric [...]

Emraclidine (CVL-231) is a selective positive allosteric modulator (PAM) of the cholinergic M4 muscarinic receptor (GCPR) and is the only selective M4 PAM in clinical development . The molecule was highlighted by Cerevel at JPM ‘23 as it has shown promising early results in schizophrenia with several Ph. II trials enrolling ( [...]

“Compound 25” is a selective, CNS-penetrant, ATP-competitive LRRK2 inhibitor that entered preclinical candidate enabling studies but was discontinued for undisclosed reasons. The molecule possesses two interesting chemical features: a “bow-tie” spirocyclopropyl group that made a significant impact on potency and overall properties [...]

A newly disclosed sGC activator in Ph. II for CKD/DKD. This month, researchers at BI reported promising preclinical results for a newly disclosed sGC activator, BI-685509, which is in several Ph. II trials including for treatment of chronic kidney disease (CKD) and diabetic kidney disease (DKD) ( NCT04736628 , NCT04750577 ). In rodents, the [...]

DN-1289 is a CNS-penetrant, ATP-competitive DLK/LZK-selective dual kinase inhibitor intended to treat amyotrophic lateral sclerosis (ALS). The molecule is structurally closely related to Genentech’s recent Ph. I candidate, GDC-0134. Dual leucine zipper kinase (DLK) and leucine zipper-bearing kinase (LZK) are... [...]

Toward an oral, once-daily non-peptide STT2 agonist. Paltusotine a novel oral somatostatin receptor 2 (SST2) agonist and Crinetics’ lead investigational drug, is intended to treat acromegaly and neuroendocrine tumors (NETs) in carcinoid syndrome. Both diseases have been treated with surgery and injectable somatostatin [...]

SPR720 (pVXc-486) is an oral prodrug of a dual inhibitor of the bacterial DNA gyrase and topoisomerase IV ATPase catalytic domains, GyrB and ParE . The molecule was in-licensed by Spero Therapeutics , a 2014 “Fierce 15” startup , from Vertex ( WO2014014845A1 , US20140031318 ), and is now Spero’s lead development program after [...]

What is it? Compound 49 is an orally available CD73 inhibitor with dose-dependent PK/PD and an immune-mediated antitumor mechanism of action. The molecule is highly potent in human plasma (0.38 nM), and despite having a high free fraction (42% unbound) and possessing several highly polar or charged groups, rings, hydrogen bond acceptors and [...]

In 2022 there were 36 novel small molecule and large molecule drugs approved by the FDA, including 18 first-in-class drug approvals. This page contains posters and reviews of the science behind each molecule including the: 19 small molecule drug approvals (excluding atoms) 17 large molecule drug approvals (click to jump to poster) 9 first in [...]

Artificial Intelligence (AI) is revolutionizing data processing, with applications to drug discovery ranging from automating cellular imaging to modeling protein folding . Although numerous startups are developing methods to apply AI-driven drug discovery to develop proprietary assets, a remaining challenge is making these powerful tools [...]

Futibatinib (Lytgobi) is a rare alkyne-containing, irreversible FGFR1-4 inhibitor that received accelerated approval from the FDA in September 2022. Structurally distinct from other approved FGFR2/3 inhibitors, futibatinib treats a range of FGFR-aberrant tumors, including those with fusions or TKI-resistant mutants like the V565I/L gatekeeper [...]

Billion-Dollar Molecules: Etavopivat, an Allosteric PKR Kinase Activator for Sickle Cell Disease Abstract. Novo Nordisk has acquired Forma Therapeutics for $1.1B for its primary investigational drug, etavopivat. Etavopivat, a past Molecule of the Month , is an oral, once-daily allosteric activator of pyruvate kinase-R (PKR), which is [...]

Omidenepag isopropyl (Omlonti) is a prodrug of a prostaglandin E2 (EP2) receptor agonist that reduces pressure in the eye. Upon topical administration to the eye, the molecule penetrates the lipophilic and negatively charged corneal epithelium and is converted to the pharmacologically active form by the enzyme carboxylesterase-1. The [...]

The first, approved non-covalent BTKi, a next-generation oral SERD, a bioactive metabolite of a GHSR1a inverse agonist with the same therapeutic effect but different MOA to its parent are just some of the examples for this month's MOTM. Learn more about the molecules by navigating to the full reviews on the right which cover: why the molecules matter, how they were discovered, the key steps behind optimization, how they work, why the targets were chosen, any interesting toxicology and clinical data, and more. Sign up for our free weekly newsletter here to get more content like this straight to...

sAC as a target for male contraception. Soluble adenylyl cyclase (sAC) is one of several ACs that catalyze the cyclization of ATP to form cyclic adenosine monophosphate (cAMP). cAMP is the second messenger in several signaling pathways including that which activates sperm to be capable of fertilizing eggs (“ capacitation ”). The target is [...]

Toward a first-in-class DGAT2 inhibitor for the treatment of NASH. Hepatic triglyceride (TG) accumulation is a symptom of non-alcoholic fatty liver disease ( NAFLD ), which can progress to non-alcoholic steatohepatitis ( NASH ), which is characterized by hepatocyte damage, inflammation and collagen deposits (fibrosis). NASH has been estimated [...]

An oral, brain-penetrant splicing modulator targeting ELP1. Incorrect splicing of the Elongator complex protein 1 (ELP1) gene causes Familial Dysautonomia (FD), a neurodegenerative disease that results in uncoordinated movement, blindness through retinal degeneration, and risk of unexplained sudden death, among other symptoms. A single T-to-C [...]

A first-in-class diazo-prodrug for the treatment of solid tumors. Sirpiglenastat (DRP-104) (Johns Hopkins/Dracen Pharmaceuticals) is a dual prodrug of 6-diazo-5-oxo-l-norleucine (DON), a diazoketone-based glutamine irreversible antagonist used to suppress cancer cell metabolism. Rapidly growing cancer cells depend on glutamine as an energy [...]