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Preclinical data highlight company’s fourth discovery stage program, a novel potent and selective KRAS(ON) inhibitor Updated preclinical data from CGT6297, Cogent’s H1047R mutant-selective PI3Kα inhibitor demonstrates robust inhibition of downstream signaling and efficacy WALTHAM, Mass. and BOULDER, Colo., Oct. 23, 2024 (GLOBE NEWSWIRE) -- Cogent Biosciences, Inc. (Nasdaq: COGT), a biotechnology company focused on developing precision therapies for genetically defined diseases, today announced the addition of a potent and selective KRAS inhibitor to its pipeline. 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 International Symposium on Molecular Targets and Cancer Therapeutics taking place in Barcelona, Spain October 23-25, 2024. “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 DetailsThe 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 MutationsSession Date and Time: Wednesday, October 23, 2024 – 12.00 - 19.00 CESTLocation: Exhibition Hall, Centre de convencions internacional Barcelona (CCIB), Barcelona, SpainPoster Number: PB108Abstract 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 CESTLocation: Exhibition Hall, Centre de convencions internacional Barcelona (CCIB) Barcelona, SpainPoster Number: PB133Abstract 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 ConferenceCogent 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. About Cogent Biosciences, Inc.  Cogent Biosciences is a biotechnology company focused on developing precision therapies for genetically defined diseases. The most advanced clinical program, bezuclastinib, is a selective tyrosine kinase inhibitor that is designed to potently inhibit the KIT D816V mutation as well as other mutations in KIT exon 17. KIT D816V is responsible for driving systemic mastocytosis, a serious disease caused by unchecked proliferation of mast cells. Exon 17 mutations are also found in patients with advanced gastrointestinal stromal tumors (GIST), a type of cancer with strong dependence on oncogenic KIT signaling. In addition to bezuclastinib, the Cogent Research Team is developing a portfolio of novel targeted therapies to help patients fighting serious, genetically driven diseases initially targeting mutations in FGFR2, ErbB2, PI3Kα and KRAS. Cogent Biosciences is based in Waltham, MA and Boulder, CO. Visit our website for more information at www.cogentbio.com. Follow Cogent Biosciences on social media: X (formerly known as Twitter) and LinkedIn. Information that may be important to investors will be routinely posted on our website and X.  Forward Looking StatementsThis press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, including, but not limited to, statements regarding the potential for CGT6297 to be a best-in-class H1047R mutant-selective PI3Kα inhibitor, the expectation that the company will initiate IND-enabling studies for CGT6297 in 2025, and the potential for the company’s KRAS program to produce a best-in-class KRAS(ON) inhibitor with pharmacological properties differentiated from existing compounds in the class and without the potential liabilities of molecules in the class. The use of words such as, but not limited to, "anticipate," "believe," "continue," "could," "estimate," "expect," "intend," "may," "might," "plan," "potential," "predict," "project," "should," "target," "will," or "would" and similar words expressions are intended to identify forward-looking statements. Forward-looking statements are neither historical facts nor assurances of future performance. Instead, they are based on our current beliefs, expectations and assumptions regarding the future of our business, future plans and strategies, our clinical results, the rate of enrollment in our clinical trials and other future conditions. New risks and uncertainties may emerge from time to time, and it is not possible to predict all risks and uncertainties. No representations or warranties (expressed or implied) are made about the accuracy of any such forward-looking statements. We may not actually achieve the forecasts or milestones disclosed in our forward-looking statements, and you should not place undue reliance on our forward-looking statements. Such forward-looking statements are subject to a number of material risks and uncertainties including but not limited to those set forth under the caption "Risk Factors" in Cogent's most recent Quarterly Report on Form 10-Q filed with the SEC. Any forward-looking statement speaks only as of the date on which it was made. Neither we, nor our affiliates, advisors or representatives, undertake any obligation to publicly update or revise any forward-looking statement, whether as result of new information, future events or otherwise, except as required by law. These forward-looking statements should not be relied upon as representing our views as of any date subsequent to the date hereof. Contact:Christi WaarichSenior Director, Investor Relationschristi.waarich@cogentbio.com617-830-1653

The enzyme PI3K plays a critical role in cell migration. Scientists have long understood this function. But researchers have recently unveiled that a subunit of this enzyme also has the ability to slam on the breaks to this process. A group of researchers have expanded conventional knowledge on a critical enzyme that controls cell migration. In a recent publication in the journal Nature Communications, they reported that phosphoinositide 3-kinase (PI3K) not only acts as an accelerator to prompt cell motility, but it also has a built-in brake mechanism that impedes migration. "PI3K is a major signaling enzyme that has been extensively studied for over 30 years due to its roles in fundamental cellular functions like growth, survival, movement and metabolism," points out Hideaki Matsubayashi, lead author of the study and assistant professor at Tohoku University's Frontier Research Institute for Interdisciplinary Sciences (FRIS). "It plays a critical part in cell migration and invasion, something that, when dysregulated, can cause many pathologies. Our work revealed that PI3K can also actively restrain these same migratory processes through a separate non-catalytic endocytic mechanism originating from its p85β subunit." Using a combination of bioinformatics, molecular modeling, biochemical binding assays and live-cell imaging, Matsubayashi and his colleagues demonstrated that a disordered region within p85β's inter-SH2 domain directly binds to the endocytic protein AP2. This part of PI3K can activate a cellular process that pulls certain molecules into the cell, and it does so without needing the enzyme's typical lipid-modification function. When the researchers disrupted the binding, the mutated p85β did not function as it should. Instead of regulating cell movement through its brake mechanism, it built up in specific sites within the cell. This leads to cells moving faster and more persistently, indicating a loss of the brake mechanism's control over cell migration. "Remarkably, this single PI3K enzyme has opposing accelerator and brake pedals built into its molecular framework," added Matsubayashi. "The endocytic mechanism helps regulate PI3K's activity to ensure that cell movement is controlled at the right times and in the right places for important biological processes." This braking role was found to be specific to just the p85β subunit. And since the p85β subunit of PI3K is linked to cancer-promoting properties, deeper understanding of PI3K regulation and its isoform specificity could lead to novel therapeutic strategies, such that selectively inhibit the cancerous aspect of PI3K, while preserving the normal functions of PI3K in healthy cells.

Novel EGFR-sparing, brain-penetrant ErbB2 inhibitor demonstrates superior efficacy profile reaching 80% brain penetrance with potent coverage of key mutations inadequately addressed by currently approved therapies Novel, H1047R mutant-selective PI3Kα inhibitor, disclosed as third Cogent discovery stage program, demonstrates high clinical target engagement without metabolic dysfunction commonly associated with molecules in the class WALTHAM, Mass. and BOULDER, Colo., Dec. 07, 2023 (GLOBE NEWSWIRE) -- Cogent Biosciences, Inc. (Nasdaq: COGT), a biotechnology company focused on developing precision therapies for genetically defined diseases, today presented updated preclinical data from its potent, selective and brain penetrant ErbB2 inhibitor program along with initial preclinical data from its newly disclosed H1047R mutant-selective PI3Kα inhibitor discovery program at the 2023 San Antonio Breast Cancer Symposium (SABCS), taking place December 5-9, 2023 at the Henry B. González Convention Center in San Antonio, Texas. The posters can be found in the ‘Posters and Publications’ portion of the Cogent website. “Broadening our pipeline of potential best-in-class targeted therapies remains key to our long-term strategy, and we are excited to provide an update on our selective, EGFR-sparing ErbB2 inhibitor, which features exceptional potency, half-life and oral bioavailability with potentially best-in-class brain penetrance to enable inhibition of mutations in CNS tissue,” said Andrew Robbins, Cogent’s President and Chief Executive Officer. “In addition, we are pleased to present initial data on our effort to design a potent H1047R mutant-selective PI3Kα inhibitor. This program aligns with our mission of creating best-in-class targeted therapies for patients with genetically defined diseases and is complementary to our efforts focused on the development of bezuclastinib in advanced and nonadvanced systemic mastocytosis and GIST.” ErbB2 Inhibitor Presentation ID: PO3-26-02Title: Identification of a novel, brain penetrant, EGFR sparing, ErbB2 inhibitor with activity against oncogenic ErbB2 mutationsSession: Poster Session 3Date: Thursday, December 7, 2023Time: 12:00 PM - 2:00 PM CT (1:00 PM – 3:00 PM ET) Cogent is developing a potential best-in-class EGFR-sparing, brain-penetrant ErbB2 inhibitor that includes coverage of key mutations (YVMA, S310F, V842I, L755S) inadequately addressed by currently approved therapies. Activating mutations in the ErbB2 gene have been identified in multiple cancers and demonstrate a tumorigenic role similar to that of ErbB2 amplification. The poster presented today shows that CGT4255 demonstrated low nM potency against ErbB2 wild-type and oncogenic ErbB2 mutations with 100-fold selectivity over wild-type-EGFR. In addition to impressive selectivity across a broad range of kinases, receptors and ion channels, CGT4255 has exceptional half-life in human whole blood and liver cytosol fractions. Dose ascending PK data in mice showed low clearance and high oral bioavailability at all doses, with best-in-class 80% brain penetrance at 100 mg/kg. Maximum inhibition of pErbB2 was observed at a 30 mg/kg PO dose in both NIH/3T3 ErbB2-YVMA and ErbB2-L755S tumor models, with complete regressions at 100 mg/kg PO BID in the NIH3T3 ErbB2-L755S TGI model and was well tolerated. These advances continue to highlight a favorable profile for optimal clinical efficacy. PI3Kα Inhibitor Presentation ID: PO3-26-01Title: Preclinical in vitro and in vivo characterization of a novel, wild-type-sparing, PI3Kα H1047R mutant-selective inhibitorSession: Poster Session 3Date: Thursday, December 7, 2023Time: 12:00 PM - 2:00 PM CT (1:00 PM – 3:00 PM ET) Cogent is developing a potential best-in-class, wild-type-sparing, PI3Kα inhibitor that provides coverage for the H1047R mutation, which affects >30,000 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. PI3Kα mutations are highly prevalent in many solid tumors and are present in 36% of all breast cancer patients. The approved agents for these patients often lead to dose limitations, resulting from activity against wild-type PI3Kα. The poster presented today highlights that CGT4824 is an allosteric inhibitor of PI3K, was well tolerated in the tumor growth inhibition efficacy models and has been profiled as lead series exemplar based on its selectivity for H1047R over WT PI3K. CGT4824 demonstrated low nM potency in H1047R mutant PI3K cell lines, differentiated dose ascending PK in mice with high bioavailability and low clearance. CGT4824 also showed >95% inhibition of pAKT in a H1047R PD model, importantly without increases in insulin or C-peptide. Its efficacy profile was superior to a clinically-relevant dose of alpelisib in the NCI H1048 mouse tumor growth inhibition model. Additional lead series analogs were also described, highlighting our more recent advances toward increasing selectivity and potency against H1047R mutants. About Cogent Biosciences, Inc.Cogent Biosciences is a biotechnology company focused on developing precision therapies for genetically defined diseases. The most advanced clinical program, bezuclastinib, is a selective tyrosine kinase inhibitor that is designed to potently inhibit the KIT D816V mutation as well as other mutations in KIT exon 17. KIT D816V is responsible for driving systemic mastocytosis, a serious disease caused by unchecked proliferation of mast cells. Exon 17 mutations are also found in patients with advanced gastrointestinal stromal tumors (GIST), a type of cancer with strong dependence on oncogenic KIT signaling. In addition to bezuclastinib, the Cogent Research Team is developing a portfolio of novel targeted therapies to help patients fighting serious, genetically driven diseases initially targeting mutations in FGFR2, ErbB2 and PI3Ka (genes/pathways). Cogent Biosciences is based in Waltham, MA and Boulder, CO. Visit our website for more information at www.cogentbio.com. Follow Cogent Biosciences on social media: X (formerly known as Twitter) and LinkedIn. Information that may be important to investors will be routinely posted on our website and X. Forward Looking StatementsThis press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, including, but not limited to, statements regarding the company's business and operations, as well as the potential benefits of the company’s ErbB2 and PI3Kα inhibitor programs. The use of words such as, but not limited to, "anticipate," "believe," "continue," "could," "estimate," "expect," "intend," "may," "might," "plan," "potential," "predict," "project," "should," "target," "will," or "would" and similar words expressions are intended to identify forward-looking statements. Forward-looking statements are neither historical facts nor assurances of future performance. Instead, they are based on our current beliefs, expectations and assumptions regarding the future of our business, future plans and strategies, our clinical results, the rate of enrollment in our clinical trials and other future conditions. New risks and uncertainties may emerge from time to time, and it is not possible to predict all risks and uncertainties. No representations or warranties (expressed or implied) are made about the accuracy of any such forward-looking statements. We may not actually achieve the forecasts or milestones disclosed in our forward-looking statements, and you should not place undue reliance on our forward-looking statements. Such forward-looking statements are subject to a number of material risks and uncertainties including but not limited to those set forth under the caption "Risk Factors" in Cogent's most recent Quarterly Report on Form 10-Q filed with the SEC. Any forward-looking statement speaks only as of the date on which it was made. Neither we, nor our affiliates, advisors or representatives, undertake any obligation to publicly update or revise any forward-looking statement, whether as result of new information, future events or otherwise, except as required by law. These forward-looking statements should not be relied upon as representing our views as of any date subsequent to the date hereof. Contact:Christi WaarichSenior Director, Investor Relationschristi.waarich@cogentbio.com617-830-1653