On October 23, 2024 Cogent Biosciences, Inc. (Nasdaq: COGT), a biotechnology company focused on developing precision therapies for genetically defined diseases, reported the addition of a potent and selective KRAS inhibitor to its pipeline (Press release, Cogent Biosciences, OCT 23, 2024, View Source [SID1234647335]). Preclinical data from this program as well as its newly announced H1047R mutant-selective PI3Kα clinical candidate will be presented in two poster presentations at the 2024 EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) International Symposium on Molecular Targets and Cancer Therapeutics taking place in Barcelona, Spain October 23-25, 2024.

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"Our Research team continues to make amazing progress, and we are excited to announce our third clinical candidate and fourth preclinical program today," said Andrew Robbins, Cogent’s President and Chief Executive Officer. "Building upon earlier data presentations and recent advancements in the field, our first poster describes the properties of CGT6297, which we believe has the potential to emerge as a best-in-class H1047R mutant-selective PI3Kα inhibitor. Separately, for the first time, we outline our progress toward developing a potential best-in-class KRAS(ON) inhibitor, which in addition to its mechanistic attributes, has pharmacological properties differentiated from existing compounds in the class. Each of these programs align with our long-term strategy of creating and developing best-in-class molecules with the potential to have a broad impact on patients with genetically defined diseases."

Poster Details
The posters can be accessed in the ‘Posters and Publications’ page of Cogent’s website.

Title: Identification of a Pan KRAS(On) Inhibitor with Selectivity Over KRAS over H/NRAS and pM Activity Across Prevalent KRAS Mutations
Session Date and Time: Wednesday, October 23, 2024 – 12.00 – 19.00 CEST
Location: Exhibition Hall, Centre de convencions internacional Barcelona (CCIB), Barcelona, Spain
Poster Number: PB108
Abstract Number: 120

Mutations in KRAS are among the most prevalent mutations found in cancer, occurring most often in colorectal cancer, non-small cell lung cancer and pancreatic cancer. The poster presented today describes Cogent’s internally-developed pan KRAS(ON) inhibitor with selectivity over HRAS and NRAS and picomolar (pM) activity across KRAS mutations without the potential liabilities of molecules in the class. Following oral administration, CGT6737 demonstrated robust PK/PD and tumor growth inhibition with 90% PD inhibition in mouse xenograft models. Lead optimization of CGT6737 is ongoing.

Title: Preclinical Characterization of a Novel PI3Kα H1047R Mutant Selective Inhibitor
Session Date and Time: Wednesday, October 23, 2024 – 12.00 – 19.00 CEST
Location: Exhibition Hall, Centre de convencions internacional Barcelona (CCIB) Barcelona, Spain
Poster Number: PB133
Abstract Number: 145

Cogent is also developing a potential best-in-class, wild-type-sparing, PI3Kα inhibitor that provides coverage for the H1047R mutation, which affects >55,000 cancer patients each year. The phosphoinositide 3-kinase (PI3K) pathway is a key cell cycle regulating pathway that has an established role in tumor growth and development. The approved agents for these patients often lead to dose limitations, resulting from activity against wild-type PI3Kα.

The poster presented today highlights Cogent’s clinical candidate CGT6297, a potent allosteric inhibitor of PI3K, with 25-fold selectivity over PI3Kα WT. CGT6297 has high oral bioavailability and low clearance across species, providing robust inhibition of downstream signaling and efficacy in animal models. Importantly, when compared to a clinically relevant dose of a currently approved therapy in a mouse tumor model, CGT6297 demonstrated superior efficacy with no increase in insulin. IND-enabling studies are expected to be initiated in 2025.

Upcoming Investor Conference
Cogent will participate in the following upcoming investor conference:

Guggenheim Healthcare Innovation Conference – November 12, 2024 at 10:30 a.m. ET.

A live webcast of the fireside discussion will be available in the Investors & Media section of Cogent’s website at investors.cogentbio.com/events. A replay of the event will be archived on Cogent’s website for up to 30 days.