Vividion Publishes Groundbreaking Science Study on Covalent RAS-PI3Kα Inhibitors That Halt Tumor Growth
Vividion Therapeutics, Inc. (Vividion), a clinical-stage biopharmaceutical company and wholly owned, independently operated subsidiary of Bayer AG, has announced the publication of a pivotal manuscript in Science detailing the discovery and preclinical characterization of a new class of small-molecule inhibitors that selectively disrupt oncogenic signaling driven by RAS-dependent PI3Kα. The publication marks a major milestone in the ongoing effort to develop more precise, less toxic therapies targeting RAS-driven cancers—one of the most challenging and pervasive classes of human malignancies.
The paper, titled “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), presents a comprehensive body of preclinical data demonstrating how Vividion’s covalent RAS-PI3Kα inhibitors effectively block tumor growth in RAS- and HER2-driven cancers. Importantly, the compounds accomplish this by selectively blocking the interaction between RAS and PI3Kα, without disrupting essential homeostatic PI3Kα signaling—a breakthrough that could minimize the dose-limiting toxicities that have plagued previous attempts to target this pathway.
A Transformative Approach to RAS-Driven Cancers
“Vividion’s RAS-PI3Kα inhibitors exemplify a fundamentally new way of addressing RAS-dependent cancers,” said Aleksandra Rizo, M.D., Ph.D., Chief Executive Officer of Vividion. “They offer the potential to disrupt one of the most important drivers of human malignancy without the dose-limiting toxicities that have historically hindered similar efforts. 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 represent one of the most common genetic alterations in human cancers, occurring in approximately 20% of all cases. These mutations activate multiple downstream signaling pathways, most notably MAPK and PI3K, that together drive uncontrolled cellular growth and tumor progression. While numerous strategies have been developed to inhibit RAS or its downstream effectors, many have failed to achieve the necessary selectivity or safety profile required for clinical success.
Historically, therapeutic strategies aimed at simultaneously targeting the MAPK and PI3K pathways have shown promise in preclinical models but have often been hampered by severe toxicities when translated into the clinic. This limitation has created a critical unmet need for approaches that can inhibit oncogenic RAS-driven signaling without compromising the normal physiological functions of the PI3K pathway, particularly its role in glucose metabolism and homeostasis.
Breakthrough Discovery Using Chemoproteomics
Vividion’s research team tackled this problem using its covalent-first chemoproteomics platform, a proprietary technology that enables the discovery of drug candidates capable of interacting with previously undruggable protein targets. Leveraging this platform, Vividion scientists identified multiple covalent small molecules that bind to the RAS-binding domain (RBD) of PI3Kα, effectively preventing RAS from activating the enzyme’s oncogenic signaling cascade.
The discovery process involved extensive collaboration with researchers at the Francis Crick Institute, one of the world’s leading centers for cancer biology. Together, the teams validated these compounds as selective inhibitors of RAS-mediated PI3Kα activation, while ensuring that they did not interfere with the pathway’s homeostatic functions necessary for normal cellular physiology.
Preclinical data presented in Science demonstrate that one of the lead compounds significantly inhibited tumor growth in vivo without inducing the systemic toxicities typically associated with PI3K inhibition. These results confirm that selectively targeting the RAS–PI3Kα interaction, rather than PI3Kα enzymatic activity itself, could represent a paradigm shift in the treatment of RAS-mutant cancers.
Dual Targeting: RAS and HER2
An unexpected and highly significant discovery from the research was that the same covalent compounds that block RAS-mediated activation of PI3Kα also inhibit HER2-mediated activation through the same binding interface. This finding uncovers a previously unrecognized mechanism of HER2-PI3Kα signaling that could extend the therapeutic relevance of Vividion’s inhibitors to a broader range of cancers, including HER2-positive breast and gastric tumors.
“This dual mechanism opens a new therapeutic frontier,” explained Julian Downward, Ph.D., Principal Group Leader of the Oncogene Biology Laboratory at the Francis Crick Institute. “We’ve been exploring how to stop RAS interactions with cell growth pathways for many years, but side effects have held back development. 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.”
The implications of this discovery are far-reaching. HER2-positive cancers, while treatable with existing targeted therapies such as trastuzumab and pertuzumab, often develop resistance through reactivation of PI3K signaling. Vividion’s covalent inhibitors could potentially overcome this resistance by cutting off HER2’s ability to engage PI3Kα at the molecular level, thereby enhancing or complementing the effects of existing HER2-targeted agents.
Selectivity Without Compromise
One of the hallmarks of Vividion’s innovation lies in its focus on selectivity and precision. Traditional PI3K inhibitors often cause adverse effects such as hyperglycemia due to interference with PI3K’s role in insulin signaling. By contrast, Vividion’s covalent inhibitors are designed to spare normal PI3Kα activity while blocking only its pathogenic activation by RAS and HER2.
This selective mechanism was confirmed in a series of biochemical and in vivo experiments showing that normal downstream PI3Kα signaling related to glucose metabolism remained intact in treated models. At the same time, RAS-driven tumor growth was robustly suppressed.
“These data underscore the unique ability of our chemoproteomics platform to uncover previously hidden druggable sites and design molecules with exceptional precision,” said Matt Patricelli, Ph.D., Chief Scientific Officer of Vividion. “Vividion’s pioneering covalent-first 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.”
Patricelli further emphasized that Vividion’s discovery engine continues to reveal “unexpected mechanisms of action targeting well-known targets and cellular pathways,” which could broaden the landscape of therapeutic possibilities across oncology and other disease areas.
A New Class of Covalent Inhibitors
The preclinical findings published in Science represent more than a single breakthrough—they introduce a new class of covalent inhibitors capable of selectively disrupting the RAS–PI3Kα interaction, a target long considered intractable.
RAS proteins are small GTPases that act as molecular switches, transmitting growth-promoting signals from cell surface receptors like EGFR and HER2 to intracellular signaling cascades. Mutations in RAS lock the protein in an “on” state, leading to continuous cell proliferation and survival signaling. Despite decades of research, RAS itself has proven notoriously difficult to drug.
Vividion’s strategy bypasses the challenge of directly inhibiting RAS by instead targeting one of its key downstream effectors—PI3Kα—and its physical interaction site. By using covalent chemistry, which forms a durable bond between the inhibitor and its target, Vividion’s compounds achieve potent and sustained inhibition with minimal off-target effects.
These attributes make the new RAS–PI3Kα inhibitors particularly well suited for RAS-driven solid tumors, including non-small cell lung cancer (NSCLC), pancreatic ductal adenocarcinoma (PDAC), and colorectal carcinoma (CRC), where RAS mutations are most prevalent and remain a major driver of resistance to current therapies.
Clinical Advancement and Future Prospects
Building on these preclinical achievements, Vividion has advanced its RAS–PI3Kα inhibitor program into Phase I clinical development, marking the first time this specific interaction is being targeted in humans. The trial aims to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of the lead compound in patients with RAS-mutant solid tumors.
The ongoing clinical study will help validate whether the high selectivity and favorable safety profile observed in preclinical models can translate to human subjects. Early indications suggest that by maintaining normal PI3K function, the compounds could offer meaningful clinical benefit without the metabolic complications seen in traditional PI3K inhibitor therapies.
Expanding the Boundaries of Chemoproteomics
Vividion’s publication in Science underscores not only its technological capabilities but also its scientific philosophy—one rooted in chemoproteomics, covalent drug discovery, and target expansion. The company has built a powerful platform that combines high-throughput chemical screening with proteomic mapping to identify small molecules capable of binding to previously “undruggable” proteins.
This platform allows Vividion to systematically explore protein surfaces and reveal functional sites that can be modulated covalently, opening new avenues in oncology, immunology, and other therapeutic fields. The company’s success with the RAS–PI3Kα program exemplifies how this approach can translate deep biological insights into viable drug candidates.
Vividion’s discovery and preclinical validation of covalent RAS–PI3Kα inhibitors, now published in Science, represent a monumental step forward in cancer drug discovery. By specifically blocking the RAS–PI3Kα interaction without impairing PI3K’s physiological roles, these compounds offer a precision oncology strategy with the potential to transform the treatment of RAS- and HER2-driven cancers.
This innovation reflects the culmination of years of fundamental research into the molecular underpinnings of RAS signaling and the persistent pursuit of selective, effective, and safe therapies. As the program advances through clinical development, it may redefine how the scientific community approaches one of oncology’s most challenging molecular targets—providing renewed hope for patients whose cancers have long resisted conventional treatment.
At its core, Vividion’s Science publication is not just a report of scientific achievement—it’s a blueprint for the next generation of covalent, chemoproteomic-driven therapeutics capable of rewriting what is possible in the fight against cancer.
