An estimated 14% of all solid tumors harbor a PI3K-alpha mutation, second only to KRAS. Relay Therapeutics used a combination of experimental and computational tools to solve the first full-length structure of the PI3K-alpha protein, including both wild-type and mutant forms. That led to the discovery of zovegalisib as the first selective, pan-mutant, allosteric inhibitor of PI3K-alpha. The molecule spares other PI3K isoforms that trigger common side effects and has acceptable on-target tolerability for hyperglycemia. The pivotal ReDiscover-2 study in CDK inhibitor experienced HR+/HER2- breast cancer is expected to conclude in mid-2028.

Full research deep dive coming soon.

Mutations in PI3K-alpha can cause benign, non-cancerous tumors in various overgrowth syndromes collectively called vascular anomalies (VA). The favorable efficacy and tolerability profiles of zovegalisib suggest the molecule has significant potential as a chronic treatment for these conditions, although doses are likely to be lower than those used in oncology indications. There are an estimated 170,000 patients in the United States with PI3K-alpha driven VAs. Relay Therapeutics is initially focusing on an estimated patient population of 25,000 individuals affected by PI3K-related overgrowth syndrome (PROS), lymphatic malformations (LM), and venous malformations (VeM).

Full research deep dive coming soon.

An estimated 14% of all solid tumors harbor a PI3K-alpha mutation, second only to KRAS. Relay Therapeutics used a combination of experimental and computational tools to solve the first full-length structure of the PI3K-alpha protein, including both wild-type and mutant forms. That led to the discovery of zovegalisib as the first selective, pan-mutant, allosteric inhibitor of PI3K-alpha. The molecule spares other PI3K isoforms that trigger common side effects and has acceptable on-target tolerability for hyperglycemia. The company is expected to provide an update on the pivotal development plan in CDK inhibitor naive HR+/HER2- breast cancer by the end of 2026.

Full research deep dive coming soon.

Whereas NRAS-driven cancers are typically treated with pan-RAS molecules or by targeting downstream pathways with pan-RAF, MEK, or ERK inhibitors, these agents have unfavorable tolerability profiles due to the importance of RAS family proteins. Relay Therapeutics used protein motion to discover novel allosteric, cryptic pockets unique to mutant NRAS proteins. As such, RLY-8161 is the first NRAS-selective molecule in the global industry pipeline. The full commercial opportunity is dispersed across many types of solid tumors impacting an estimated 29,000 U.S. patients, but initial development may focus on colon cancer (6,500 U.S. patients), melanoma (4,300 U.S. patients), and non-small cell lung cancer (NSCLC) (2,100 U.S. patients).

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This unnamed preclinical asset is a non-inhibitory chaperone of mutant alpha-galactosidase A (α-Gal A) enzymes. Mutant α-Gal A loses its ability to break down globotriaosylceramide (Gb3). Fabry disease is caused by the accumulation of Gb3 in organs throughout the body. However, there are hundreds of known mutations, which has thwarted attempts to develop effective treatments. This asset works by binding to and bending mutant α-Gal A enzymes into functional enzymes with more activity. As a non-inhibitory chaperone, it could be effective against dozens of common mutants and compatible with enzyme replacement therapy (ERT).

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Lirafugratinib is a highly-selective small molecule inhibitor of FGFR2, which is mutated, amplified, or fused in specific types of solid tumors. Relay Therapeutics discovered the molecule by simulating protein motion of related FGFR proteins to find a unique allosteric pocket on the FGFR2 protein. The initial indication in cholangiocarcinoma (CCA) is a relatively rare, aggressive cancer. A slightly broader tumor-agnostic opportunity could be accessed pending the results of an additional pivotal study.

Full research deep dive coming soon.

Lirafugratinib is a highly-selective small molecule inhibitor of FGFR2, which is mutated, amplified, or fused in specific types of solid tumors. Relay Therapeutics discovered the molecule by simulating protein motion of related FGFR proteins to find a unique allosteric pocket on the FGFR2 protein. The initial indication in cholangiocarcinoma (CCA) is a relatively rare, aggressive cancer. A slightly broader tumor-agnostic opportunity could be accessed pending the results of an additional pivotal study.

Full research deep dive coming soon.