Nuvalent’s lead compound, NVL-520, is an oral, brain-penetrant, TRK-sparing, and potential best-in-class ROS1 kinase inhibitor that recently entered Ph. II of the ARROS-1 trial (NCT05118789) in patients with advanced ROS1-positive NSCLC. This article highlights what makes the Nuvalent’s NVL-520 program scientifically notable, including what gives it a potential best-in-class profile as a ROS1 inhibitor, the emerging toxicology of hard-to-avoid off-targets, an interesting synthetic route to the small macrocycle, and more.

In a Drug Hunter Flash Talk, Dennis Koester, Director of Medicinal Chemistry at FibroGen, shared an adage credited to the Greek philosopher Epictetus that he wishes his younger self had learned: "We have two ears and one mouth so that we can listen twice as much as we speak." During this ongoing video series, other scientists, including Chris Burns, Christian Gampe, Katrina (Kate) Jackson, Dafydd Owen, Prof. Richard (Rick) Silverman, and Prof. Andrew Wilks, also talked about what they wished they had learned earlier in their careers.

PF-9363 (CTx-648) is a first-in-class, oral inhibitor of the KAT6A/B histone lysine acetyltransferases (HATs) for the treatment of ER+/luminal & KAT6A+ breast cancer discovered by Melbourne’s Cancer Therapeutics CRC (CTxT) and Pfizer, San Diego. This article discusses why the molecule is scientifically notable in drug discovery for epigenetic targets and transferable scientific insights from its decade-long KAT6 campaign including its target rationale, hit-finding and lead optimization, synthesis and relevant clinical data.

Peptidic GLP-1R agonists have received significant media coverage over the past year. Shortages of the semaglutide-based injectable diabetes medication Ozempic, which accounts for 40% of GLP-1R agonist US market share, have even emerged, driven by overwhelming demand for the weight loss formulation Wegovy, both for treatment of obesity and for short-term weight loss popularized by celebrities on social media. This article reviews the science of danuglipron, recent news, and what makes it different.

Whereas covalent drugs were once considered risky for indications other than cancer due to the potential for idiosyncratic drug-induced liver injury and other toxicities, concerns appear to have softened as an increasing number of non-oncology covalent inhibitor programs have achieved successful outcomes. Here we highlight several recent anecdotes in covalent inhibitor drug discovery that seem to reflect these changing attitudes, including billion-dollar acquisitions and approvals outside oncology, and a few modern examples that showcase the increasingly rich science in this area.

In 2022, Turning Point Therapeutics ($TPTX) was acquired by BMS for a whopping $4.1 billion in cash. In November 2023, the most advanced molecule from Turning Point, repotrectinib, was approved for the treatment of ROS1+ NSCLC. This article explores the science behind repotrectinib, what made Turning Point so valuable, how we know, and what's next. [...]

Chugai’s PCO371 is an oral, biased agonist and "molecular wedge" of the class B GPCR, PTHR1, that first entered development for hypoparathyroidism in 2015 (NCT02475616). While Class A GPCRs, which typically have compact ligandable pockets are the most common targets for approved drugs, Class B GPCRs like PTHR1, GLP-1R, and CGRP are notoriously difficult to drug since they normally bind large peptides with long transmembrane tunnels that are not easily bound by small molecules. This article explains what makes PCO371 a big deal for GPCR drug discovery.

The team reviews hundreds of compounds from thousands of papers, press releases, and other sources each month to select candidates for Molecules of the Month. Here we have compiled a table of >70 additional molecules that were of interest in October 2023 but we did not have space for in MOTM. A few highlights are also discussed, including Novartis’s Werner helicase (WRN) inhibitor, APJ agonist AMG985 molecular glue degrader golcadomide, and more in the full article.

TEAD1-4, nuclear transcription factors that are key effectors of the Hippo pathway, have become of increased recent interest in part due to the potential for TEAD inhibitors to synergize with RAS inhibition. GNE-7883, a pan-TEAD allosteric inhibitor tool from Genentech demonstrated in vivo proof-of-concept for combination therapy with a KRAS(G12C) inhibitor. This article highlights the rational design of an allosteric pan-TEAD inhibitor from a FRET-based HTS, the activities of GNE-7883 in YAP/TAZ-dependent cancers, and the potential applications of TEAD inhibitors in precision oncology.

The Hippo pathway is a well-known regulator of tissue growth and organ size and gets its name from the Hippo kinase (Hpo in Drosophila, MST1/2 in humans), which when mutated leads to “hippopotamus”-like tissue overgrowth. Recently, industry interest in the pathway has increased thanks to several independent studies in 2023, and the field appears to be at an important inflection point for drug discovery. Here we review current efforts and therapeutic hypotheses for drugging the TEAD transcription factors in cancer, including clinical molecules, paralog-selective molecules, and TEAD degraders.

Zunsemetinib (ATI-450, CDD-450) is a p38α- MK2 complex inhibitor discovered by Confluence Technologies and developed by Confluence spinout, Aclaris Therapeutics. The molecule has a unique molecular glue-like mechanism of action that held promise in immunology, but sadly recent results have led to its discontinuation. This article reviews the target, its mechanism, and why it mattered.

There are three notable highlights from AbbVie this month with published details on their first-in-class PTPN2/N1 inhibitor ABBV-CLS-484, currently in Phase I trials, and their recently acquired PINK1 activator MTK458 for Parkinson’s Disease. AbbVie also released details on the development of their selective MCL-1 inhibitor ABBV-467, which had disappointingly showed signs of cardiotoxicity as seen with other MCL-1 inhibitors. Also featured this month are molecular glues currently in clinical trials from Revolution Medicines and Monte Rosa Therapeutics and a pan-KRAS degrader from Boehringer In...

KIN-3248 (Kinnate Biopharma) is a next-generation, irreversible, pan-fibroblast growth factor receptor inhibitor (FGFRi) in a first-in-human (FIH) dose-escalation study (NCT05242822) in adults with advanced tumors harboring FGFR2 and FGFR3 gene alterations. The program is an excellent case study for rational covalent drug design to address kinase mutations while maintaining sufficient PK properties for oral daily dosing in humans.

Peptidic GLP-1R agonists have received significant media coverage over the past year for their astounding efficacy in several indications. GLP-1R agonists now appear to be efficacious in reducing heart disease risk and in treating certain chronic kidney diseases, expanding their likely future use. This review by Oliver Philps provides an overview of GLP-1 agonists and where they fit in the treatment of diabetes, how the peptide drugs evolved over time to today’s weight loss medications, and what to expect next...

STX-721 is an oral, covalent, mutant-selective inhibitor of EGFR and HER2 Exon 20 insertion (ex20ins) mutants, a well-validated target that saw its first approval with mobocertinib in 2022. Inhibition of wild-type (WT) EGFR is well-established to cause skin and gut toxicities, and selective inhibition of EGFR ex20ins mutants over WT may also allow greater efficacy to be seen at tolerated doses. This is an excellent case study for PK optimization with a covalent inhibitor, and [...]

There continue to be opportunities for another KRAS(G12C) inhibitor to prove itself best-in-class.

This roundup highlights twelve KRAS(G12C) molecules to know, with links to recent case studies on Drug Hunter going in more detail.

The team reviews hundreds of compounds from thousands of papers, press releases, and other sources each month to select candidates for Molecules of the Month. Based on requests from readers to see more molecules, this article contains a table of >40 additional molecules that were of interest last month but not included in MOTM, with a few highlights including off-target toxicity seen in a KRAS(G12D) program and hits on challenging target classes.

RPT193, an oral, second-generation CCR4 inhibitor from RAPT Therapeutics, is in Ph. II clinical trials (400 mg QD) to treat atopic dermatitis (AD) (NCT05399368) and asthma (NCT05935332). CCR4 has been a long outstanding therapeutic target for treating inflammatory diseases, but despite many efforts, no molecule inhibiting this receptor has progressed beyond Ph. I for these indications.