November’s Molecules of the Month features GSK’s small-molecule IBAT inhibitor designed to alleviate relentless itch, and Novartis’ TAK1 inhibitor for osteoarthritis, showcasing a fascinating drug design and delivery strategy to maximize joint concentration while minimizing systemic exposure. Additionally, we highlight a clinical-stage, long-acting inhaled ENaC inhibitor for cystic fibrosis, a highly soluble prodrug of a potent capsid assembly modulator for HBV, and innovative macrocyclic CDK7 and NLRP3 inhibitors. You can read more about the compounds that made our November 2024 Molecules of...

The 2024 SABCS brought together over 10,000 attendees from more than 100 countries, including leading academics, researchers, patient advocates, and healthcare professionals, to showcase state-of-the-art advances in breast cancer research. In our highlights, we will cover exciting clinical trial updates from this year’s symposium, including targeted molecules addressing key pathways such as CDK4, CDK2, and PI3Kα, along with advancements in next-generation oral SERDs (selective estrogen receptor degraders).

BridgeBio’s acoramidis (Attruby), an oral, second-generation stabilizer of the TTR protein, has been approved by the FDA for the treatment of ATTR-CM (transthyretin amyloid cardiomyopathy). Amyloid deposits in the heart muscle characterize the rare but potentially fatal disease. This case study reviews the history of TTR modulation, early experiments validating the therapeutic potential of TTR stabilization, the binding mechanism of acoramidis to TTR, the importance of binding enthalpy for differentiation, and the molecule’s impressive 30-month clinical data following an early scare.

As the “Guardian of the Genome,” the tumor suppressor transcription factor p53 has been a much sought-after target in oncology, with over 50% of malignancies showing mutations in p53. The p53(Y220C) mutant has been of particular interest as it creates a pocket which small molecule stabilizers are able to bind to and restore p53 function. PMV Pharma is the first to enter the clinic with their p53(Y220C) stabilizer rezatapopt, which was optimized from a hybrid of known binders and which is showing real promise against a swath of solid tumors.

Tyra Biosciences’ lead asset, TYRA-300, is a potent, selective, and orally bioavailable FGFR3 inhibitor designed to mitigate the toxicities commonly seen with pan-FGFR inhibitors. A key objective of the program was to meet the safety standards required for advancing into pediatric populations for the treatment of ACH (achondroplasia) and other skeletal dysplasias. TYRA-300 is currently being evaluated in Ph. I clinical trials for advanced urothelial cancers and other solid tumors and, importantly, has received IND clearance to initiate a Ph. II clinical trial in pediatric ACH patients.

GSK and Roche strengthened their pipelines by forming groundbreaking collaborations that target neurodegenerative diseases and transcription factors, respectively. Meanwhile, Pep2Tango Therapeutics introduced a novel obesity treatment approach, and Amgen faced scrutiny over emerging data on its obesity drug candidate MariTide. This roundup covers the details behind these headlines.

This summary of major clinical updates from November 2024 covers FDA approvals, the initiation of new clinical trials, notable trial outcomes for key drug candidates, and news on paused and discontinued trials and programs.

HRX-215 is an orally bioavailable MKK4 inhibitor for liver regeneration. In just over a decade since they discovered the dual specific kinase MKK4 as a master regulator of hepatocyte regeneration, HRX-215 completed a FIH clinical trial. This article is a fascinating case study on harnessing the liver's natural regenerative capacity, identifying key regulators of liver regeneration, and leveraging a kinase inhibitor with reported off-target activity for MKK4 as a suitable starting point, among other insights.

Our October patent highlights cover a diverse array of drug discovery IP disclosures. From piperidine-based USP19 inhibitors and small molecule GIPR antagonists for obesity to KCC2 potentiators for epilepsy, the month delivered a number of exciting IP developments. Other notable discoveries include MTA-cooperative PRMT5 inhibitors, direct-acting influenza antivirals against a novel target, Nrf2 activators for heart failure, and a slew of Polθ inhibitors for HR-deficient cancers.

IAG933 is Novartis’ potential first-in-class small molecule inhibitor of the PPI between YAP/TAZ and TEAD, currently in a Ph. I trial for solid tumors with Hippo pathway alterations. This case study not only highlights a fascinating mechanism of action but also serves as an excellent example of how to leverage structural data to inform hit selection and guide lead optimization, how to employ multiparameter optimization to circumvent cardiotoxicity liabilities, and how to redirect metabolism.

In this roundup, we present a curated selection of over 50 molecules from October that captured our team’s interest. We highlight our top picks and offer insights into what makes them stand out.

Morphic Therapeutic’s MORF-627 is an oral αvβ6 integrin inhibitor designed to treat IPF by blocking the TGFβ pathway. The Morphic team leveraged SBDD and FEP+ during lead optimization to enhance permeability and isoform selectivity. This article highlights the team’s focus on inhibiting the “bent-closed” conformation of αvβ6 as well as the linker design that led to the “chameloenicity” of the lead compound. The impressive multispecies PK and in vivo efficacy of MORF-627 in preclinical models was unfortunately accompanied by oncogenic toxicity that prevented it from reaching clinical trials.

Revumenib (Revuforj®) is approved by the FDA as an oral, first-in-class menin-MLL interaction inhibitor for acute leukemia (AL). Since inhibition of the menin-MLL fusion protein interaction is selective for AL with a KMT2A translocation, it does not compromise normal hematopoietic function. This article covers the background, optimization and clinical development that has led to the approval of this groundbreaking new drug in a hard-to-treat indication.

Check out our searchable, annotated database featuring our curated selection of the most important drug discovery patents published in October 2024.

Medicinal chemists often face cardiotoxicity issues linked to inhibition of the hERG (human ether-à-go-go-related gene) channel. In a recent Coffee Chat, Drug Hunter CEO Dennis Hu, Director for Industry Research and Relations Dennis Koester, and Senior Scientific Editor Matt Hesse discussed ways to reduce hERG risks during lead optimization. They described approaches to reduce hERG affinity while retaining on-target potency and discussed case studies of drug programs that used these strategies to eliminate their hERG issues.

The 2024 edition of MCR (Medicinal Chemistry Reviews), edited by Joachim Rudolph and Will Watkins, has just been published by the American Chemical Society MEDI Division. Featuring contributions from a global team of section editors and authors, MCR offers concise updates on a broad range of contemporary drug discovery topics, making it an invaluable resource for both aspiring and experienced medicinal chemists.

Nurix’s NX-2127 is an orally bioavailable BTK degrader that exhibits in vivo degradation across species and has advanced into first-in-human clinical trials for relapsed/​refractory B-cell malignancies. This molecule one-pager serves as a reference guide, offering an overview of the scientific significance of Nurix's NX-2127 program. It includes links to key presentations, publications, patents, preclinical and clinical PK data summaries, and more.

Understanding how a small molecule ligand binds to its target is valuable in drug discovery, because it enables more efficient optimization through structure-based design, better mechanistic understanding of molecular pharmacology, and greater confidence in the therapeutic hypothesis from both safety and efficacy perspectives. Recently, Drug Hunter highlighted methods for target identification when the target is unknown.