Discovery and Characterization of the Potent, Allosteric SHP2 inhibitor GDC-1971 for the Treatment of RTK/RAS Driven Tumors
Our DynamoTM platform and approach are creating new possibilities in drug discovery
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 a dose-limiting side effects caused by inhibition of FGFR1 and FGFR4.
Interim clinical data support RLY-4008 as the first highly selective FGFR2 inhibitor that has not shown to be limited by off-target toxicities of hyperphosphatemia (FGFR1) and diarrhea (FGFR4). These initial data also suggest RLY-4008 is safe, tolerable and drives tumor regression across multiple tumor types.
The ongoing first-in-human trial for RLY-4008 is designed to evaluate the safety, tolerability, pharmacokinetics and anti-tumor efficacy. Following a thorough assessment of the dose escalation data, the expansion portion of the trial has been initiated at a dose of 70 mg once daily.
RLY-2608 is designed to be the first allosteric, pan-mutant (H1047X, E542X and E545X) and isoform-selective PI3Kα inhibitor.
PI3Kα is the central regulator of a 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 large sequencing efforts identifies PI3Kα as the most frequently mutated kinase in cancer.
Traditionally, the development of PI3Kα inhibitors has focused on the active, or orthosteric, site. The therapeutic index of orthosteric inhibitors is limited by the lack of clinically meaningful selectivity for mutant versus WT PI3Kα and off-isoform activity. Toxicity related to inhibition of WT PI3Kα and other PI3K isoforms results in sub-optimal inhibition of mutant PI3Kα with reductions in dose intensity and frequent discontinuation. RLY-2608 is designed to overcome these limitations.
We solved the full-length cryo-EM structure of PI3Kα, performed computational long time-scale molecular dynamic simulations to elucidate conformational differences between WT and mutant PI3Kα, and leveraged these insights to support the design of RLY-2608.
The first-in-human trial for RLY-2608 is designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary antitumor activity
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.
In December 2020, we entered into a worldwide license and collaboration agreement with Genentech, a member of the Roche Group, for the development and commercialization of RLY-1971. In July 2021, Genentech initiated the cohort of RLY-1971/GDC-1971, an inhibitor of SHP2, in combination with GDC-6036, an inhibitor of KRAS G12C, in a Phase 1b trial.
Discovery Programs (5+)
While our initial focus has been on enhancing small molecule therapeutic discovery in precision oncology, protein conformational dynamics are implicated in a wide variety of therapeutic areas. We have also leveraged the power of our Dynamo platform to extend to genetic disease as well.
Our current discovery programs are focused in targeted oncology (3) and genetic disease (2).
We also continue to evaluate potential additional therapeutic areas beyond precision oncology and genetic disease that we could enter in the future.
At Relay Therapeutics, we know that patients need new medicines now. This is the driving force behind everything we do.