- Chemoproteomics screening platform identified novel covalent inhibitors that specifically disrupt RAS-mediated activation of the catalytic subunit of PI 3-kinase alpha (PI3Kα)
- Newly identified group of compounds shown to inhibit RAS-mutant and HER2 over-expressing tumors in vivo, particularly in combination with other RAS/MAPK inhibition, without causing hyperglycemia
- Related investigational therapy currently in Phase I clinical trial
SAN DIEGO--(BUSINESS WIRE)--Vividion Therapeutics, Inc. (Vividion), a clinical-stage biopharmaceutical company, and a wholly owned and independently operated subsidiary of Bayer AG, today announced the publication of a manuscript in Science describing the discovery and preclinical characterization of small molecules that inhibit RAS-dependent PI3Kα oncogenic signaling by specifically blocking the interaction between RAS and PI3Kα, without disrupting homeostatic signaling.
The article, “Covalent inhibitors of the PI3Kα RAS binding domain impair tumor growth driven by RAS and HER2” (Klebba et al., Science, Advanced Online Publication, October 2025), demonstrates the promising potential of RAS-PI3Kα inhibitors as treatments for RAS-driven cancers.
“Vividion’s RAS-PI3Kα inhibitors exemplify a fundamentally new way of addressing RAS-dependent cancers, offering the potential to disrupt one of the most important drivers of human malignancy without the dose-limiting toxicities that have historically hindered similar efforts,” said Aleksandra Rizo, M.D., Ph.D., Chief Executive Officer of Vividion. “Now in Phase I, this program underscores our ability to convert deep scientific expertise into therapeutic candidates that could help patients in need of better treatment options.”
RAS mutations, which occur in about 20% of human cancers, can lead to uncontrolled cellular growth through the activation of both the MAPK and PI3K pathways. Preclinical models have shown that simultaneously targeting these two pathways can effectively inhibit disease progression, but this approach has been hampered by dose-limiting toxicities. Vividion researchers identified multiple covalent compounds which were validated, in collaboration with the Francis Crick Institute, as selective inhibitors of RAS activation of the PI3Kα pathway. In vivo studies showed one of the compounds successfully inhibited tumor growth without disrupting the pathway’s normal downstream activity, representing a promising new approach for cancer therapy. In addition to blocking RAS-driven activation of PI3Kα, the compounds were also found to block HER2-mediated activation through the same binding site – a previously unrecognized function that could extend their potential to treat a wider range of tumors.
“We’ve been exploring how to stop RAS interactions with cell growth pathways for many years, but side effects have held back the development of treatments,” said Julian Downward, Ph.D., Principal Group Leader of the Oncogene Biology Laboratory at the Crick Institute. “Our collaborative effort has overcome this challenge by targeting the PI3Kα and RAS interaction specifically — highlighting the power of understanding chemistry and fundamental biology in designing better cancer therapies.”
Taken together, these data represent a new class of covalent inhibitors that can be used to selectively disrupt the RAS-PI3Kα interaction, potentially preventing the growth of RAS-driven tumors in patients without impacting PI3K’s normal role in glucose homeostasis.
“Vividion’s pioneering covalent-first chemoproteomics approach enabled us to discover multiple classes of PI3Kα selective small molecules, including both inhibitors as well as enhancers of RAS interaction, with potential applications in cancer and beyond,” said Matt Patricelli, Ph.D., Chief Scientific Officer of Vividion. “Our approach continues to reveal unexpected mechanisms of action targeting well-known targets and cellular pathways, expanding our understanding of cancer dependencies and pointing to new therapeutic opportunities.”
About Vividion
Vividion Therapeutics, Inc., a wholly owned and independently operated subsidiary of Bayer AG, is a clinical-stage biopharmaceutical company utilizing novel discovery technologies to unlock difficult-to-drug targets with strong disease-links, and to develop small molecule precision therapeutics for devastating cancers and immune disorders. The company’s platform has enabled it to identify hundreds of previously unknown functional pockets on well-validated protein targets implicated in a wide range of diseases, while simultaneously identifying compounds from its proprietary covalent chemistry library that interact in a highly selective manner with those pockets. The company is leveraging its proprietary chemoproteomic platform to advance a diversified pipeline of highly selective small molecule therapeutics targeting high-value, traditionally undruggable targets in oncology and immunology. For more information, please visit www.vividion.com.
Contacts
Vividion Media Contact:
Laurie Sherman, phone +1 858 630 8246
Email: media@vividion.com
