We have deployed our Dynamo platform to initially focus on the area of precision oncology. To date, we have generated several precision oncology product candidates that address previously intractable oncogenic targets. In addition, we are also advancing several early programs focused on other precision oncology and rare genetic disease targets. To date, we have not entered into partnerships to clinically develop or commercialize any of our programs.
RLY-1971 is designed to be an oral, small molecule, potent and selective inhibitor of the protein tyrosine phosphatase SHP2 that binds and stabilizes SHP2 in its inactive conformation.
SHP2 promotes cancer cell survival and growth through the RAS pathway by transducing signals downstream from receptor tyrosine kinases (RTKs). As a critical signaling node and regulator, SHP2 drives cancer cell proliferation and plays a key role in the way cancer cells develop resistance to targeted therapies.
We believe that inhibition of SHP2 could be effective as a monotherapy in cancers with specific alterations and could block a common path that cancer cells exploit to avoid killing by other antitumor agents, thus overcoming or delaying the onset of resistance to those therapies.
We are currently evaluating the safety and tolerability of RLY-1971 in a Phase 1 dose escalation study in patients with advanced or metastatic solid tumors. For more information on the trial, please click here.
RLY-4008 is designed to be an oral, small molecule, selective inhibitor of FGFR2, a receptor tyrosine kinase that is frequently altered in certain cancers.
FGFR2 is one of four members of the FGFR family, a set of closely related proteins with highly similar protein sequences and properties. Non-selective, pan-FGFR inhibitors produced by other companies have demonstrated clinical proof-of-concept in patients with intrahepatic cholangiocarcinoma bearing FGFR2 gene fusions. However, these existing FGFR therapies are constrained by hyperphosphatemia, a dose-limiting side effect caused by inhibition of FGFR1.
By applying our expertise in computational modeling and experimental structural analyses, we discovered motion-based differences between FGFR2 and other FGFR family members, and exploited these dynamic differences to develop our drug candidate. RLY-4008 is exquisitely selective for FGFR2 and has demonstrated potent FGFR2-dependent killing in cancer cell lineswhile showing minimal inhibition of other targets, including other members of the FGFR family.
Our RLY-4008 clinical development plan seeks to leverage the unique potential for enhanced tolerability and broad FGFR2 mutational coverage to rapidly generate proof-of-concept in molecularly defined patient subsets.
PI3Kα is the central regulator of a cellular signaling pathway that has been linked to a diverse group of cellular functions related to cancer including cell growth, proliferation and survival. Data collected as a part of Foundation Medicine Insights and other data sources identifies PI3Kα as the most frequently mutated kinase in cancer.
Current inhibitors of PI3Kα target the catalytic site of PI3Kα and are very challenging for many patients to tolerate given a vast array of toxicities caused by inhibition of wild-type PI3Kα and inhibition of other PI3K isoforms.
Our approach to the challenge of mutant selectivity led us to solve the first full-length protein structure of PI3Kα, which provided us with unprecedented insights into the mechanism of activation of PI3Kα and the impact of mutations on its function. We are now developing a franchise of programs that selectively target the cancer-associated mutant variants of PI3Kα that spare the wild-type protein.
We are deploying our Dynamo platform to advance three additional discovery-stage precision oncology programs. As with our lead programs, these programs leverage insights into protein conformational dynamics to address high-value, genetically validated oncogenes that previously have been intractable to conventional drug discovery approaches. The capabilities for our Dynamo platform in protein visualization can be applied to multiple therapeutic areas beyond precision oncology. We are continuing to leverage the power of our Dynamo platform to further diversify our pipeline by extending our approach to address genetically validated targets in monogenic diseases with two discovery-stage programs, where genetic alterations lead to disease-causing defects in protein conformational dynamics.
In the early 1990s, the pharmaceutical industry was transformed by the widespread adoption of structure-based drug design—a process in which the three-dimensional structure of a given target protein is used to guide the design of drugs that bind to that target.
Until recently, this process has been based largely on static “snapshots” of the target protein. Recent advances in experimental and computational technologies, however, have begun to reveal the dynamic structural changes undergone by such proteins, which are often central to their function.
The team and the tools that Relay has assembled are allowing it to observe the motion of pharmaceutically relevant target proteins and to predict how they would interact with hypothetical drug molecules. In particular, our approach is creating new opportunities for the design of powerful and selective allosteric drugs, which interact with one part of a target protein in order to change the behavior of another part.
By placing protein motion at the heart of drug discovery, Relay is pursuing what it believes will be a fundamental paradigm shift within the pharmaceutical industry, ushering in a new generation of drugs with the potential to improve and extend the lives of millions of patients.