c-Cbl

Casitas B-lineage lymphoma b (Cbl/b) is an E3 ubiquitin ligase that has been shown to be a key regulator of the activation of T and natural killer (NK) cells in the absence of CD28 costimulation GRC 65327 has been identified by IGI as a novel, nanomolar potent, selective, and orally bioavailable Cbl/b inhibitor NEW YORK, Sept. 30, 2024 (GLOBE NEWSWIRE) -- Ichnos Glenmark Innovation (IGI), an alliance between Ichnos Sciences Inc., a global fully integrated clinical-stage biotech company developing multispecifics™ in oncology, and Glenmark Pharmaceuticals Ltd., today announced a Cooperative Research and Development Agreement (CRADA) with the National Cancer Institute (NCI), a part of the National Institutes of Health (NIH) in the United States. Under the CRADA, IGI and NCI will collaborate on evaluating IGI's proprietary Cbl/b small molecule, GRC 65327. “GRC 65327 is a best-in-class, novel, selective, orally active, Cbl-b inhibitor that demonstrates good in vitro potency, in vivo efficacy and an acceptable non-clinical toxicity profile,” said Nagaraj Gowda, PhD, Vice-President, Head of Small Molecule Research at IGI. In the research covered by the CRADA, NCI will first characterize and then test GRC 65327 in immune-competent models of triple-negative breast cancer (TNBC) with the intent of generating preclinical data to support a clinical trial in late-stage TNBC at NCI. Stan Lipkowitz, M.D., Ph.D., Chief of Women's Malignancies Branch, Deputy Director of the Center for Cancer Research at the NCI, and his team will build on their substantial achievements in early Cbl/b research that include initially cloning the gene and having identified Cbl/b’s role as a negative regulator of the adaptive immune system. “Small molecule inhibitors of Cbl/b may enhance adaptive anti-tumor activity by increased signaling through the costimulatory pathway in T cells and innate immunity via enhanced NK cell activity,” said Dr. Lipkowitz. “My group will test the novel Cbl/b inhibitor developed by IGI in in vitro, cell-based, and in vivo mammary cancer models to evaluate its activity as Cbl/b inhibitors and modulators of adaptive and innate immune response to breast cancers.” “We believe in the power of collaboration to drive innovation. Partnering with Dr. Lipkowitz and the NCI to advance our scientific understanding of GRC 65327 is expected to speed its potential development in TNBC, a cancer with few effective treatment options for patients,” said Cyril Konto, M.D., President, Executive Director and CEO of IGI. “In addition, the work of Dr. Lipkowitz’s laboratory in late-stage TNBC complements the program IGI has developed to advance GRC 65327 in other solid tumors.” About IGI’s GRC 65327–Casitas B-Lineage Lymphoma b (Cbl/b) Program: Casitas B-lineage lymphoma b (Cbl/b) is an E3 ubiquitin ligase that has been identified as a key inhibitor of T and NK cells activation in the absence of CD28 costimulation, regulate immune cells activity in PD-1, CTLA4 and TIGIT positive cells. As an intracellular master regulator, Cbl/b inhibition may lead to robust immune cell activation in immune-suppressed tumor microenvironment and induce strong single-agent activity. A first-in-human clinical trial in patients with relapsed/refractory solid tumor indications is expected to start in early 2025. IGI plans to present the preclinical data package for GRC 65327 at an upcoming scientific conference. About Ichnos Glenmark Innovation: Ichnos Glenmark Innovation (IGI) is an alliance between Ichnos Sciences Inc., a global fully-integrated clinical-stage biotech company developing multispecifics™ in oncology, and Glenmark Pharmaceuticals Ltd. (Glenmark), with the aim to accelerate new drug discovery in cancer treatment. IGI combines Ichnos' research and development proficiencies in novel biologics with those of Glenmark’s in new small molecules to continue developing cutting-edge therapy solutions that treat hematological malignancies and solid tumors. Harnessing the combined proficiency of over 150 scientists and a robust pipeline of novel molecules, this collaboration will leverage the capabilities of its three global centers of innovation spread across the USA, Switzerland and India to propel Innovation. For more information, visit www.iginnovate.com. For more information, please contact: IGI Corporate Communications Team Corporate.communications@iginnovate.com

Preclinical data highlight potential target engagement biomarkers to support clinical evaluation of CBL-B inhibitors BOSTON, Nov. 3, 2023 /PRNewswire/ -- HotSpot Therapeutics, Inc., a biotechnology company pioneering the discovery and development of oral, small molecule allosteric therapies targeting regulatory sites on proteins referred to as "natural hotspots," today announced the presentation of additional preclinical data from the Company's Casitas B-lineage lymphoma proto-oncogene (CBL-B) program in a poster presentation at the 2023 Society for Immunotherapy of Cancer (SITC) Annual Meeting. "Our enthusiasm for the therapeutic potential of HST-1011, a potential best-in-class CBL-B inhibitor, is partly driven by our belief that it can drive single-agent biological activity," said Timothy Reilly, Ph.D., Chief Development Officer of HotSpot. "Understanding which peripheral biomarkers are associated with this biology and the reliability of their measurement is critical to our characterization of of HST-1011's activity in patients as we advance our ongoing Phase 1/2 study." The presentation describes preclinical data in which HotSpot CBL-B inhibitors were evaluated in both in vitro and in vivo settings to identify and then characterize a repertoire of potential proximal biomarkers of CBL-B inhibitory activity. Several proteins, including phosphorylated ZAP70, Notch1 and IGF1R, showed robust dose-dependent effects and were further assessed for their reliability and potential feasibility for use in a clinical setting. The results provide support for their potential use in evaluating HST-1011 in our ongoing Phase 1/2, open-label, clinical study designed to evaluate HST-1011 alone and subsequently in combination with Regeneron's anti-PD-1 therapy, Libtayo® (cemiplimab), in patients with advanced solid tumors that are relapsed on or are refractory to anti-PD(L)-1 or standard of care therapies. Information on this clinical trial can be found on (NCT05662397). About HST-1011 HST-1011 is an investigational orally bioavailable, selective, small molecule allosteric inhibitor of CBL-B, an E3 ubiquitin protein ligase critically involved in immune cell response. Because CBL-B functions as a master regulator of effector cell (T cell and natural killer cell) immunity, its inactivation removes its endogenous negative regulatory functions to substantially enhance anti-tumor immunity. Preclinical data has demonstrated HST-1011's ability to bind to and inhibit a natural hotspot on CBL-B, yielding the activation and propagation of a targeted anti-tumor immune response. Enabled by HotSpot's proprietary Smart Allostery™ platform, HST-1011 is designed with tight binding, low nanomolar potency, a slow dissociation rate from the target to enable sustained pharmacology, and greater selectivity for CBL-B relative to C-CBL. About HotSpot Therapeutics, Inc. HotSpot Therapeutics, Inc. is pioneering a new class of allosteric drugs that target certain naturally occurring pockets on proteins called "natural hotspots." These pockets are decisive in controlling a protein's cellular function and have significant potential for new drug discovery by enabling the systematic design of potent and selective small molecules with novel pharmacology. The Company's proprietary Smart Allostery™ platform combines computational approaches and AI-driven data mining of large and diverse data sets to uncover hotspots with tailored pharmacology toolkits and bespoke chemistry to drive the rapid discovery of novel hotspot-targeted small molecules. Leveraging this approach, HotSpot is building a broad pipeline of novel allosteric therapies for the treatment of cancer and autoimmune diseases. To learn more, visit . Investor & Media Contact: Natalie Wildenradt [email protected] SOURCE HotSpot Therapeutics

BOSTON, Sept. 27, 2023 /PRNewswire/ -- HotSpot Therapeutics, Inc., a biotechnology company pioneering the discovery and development of oral, small molecule allosteric therapies targeting regulatory sites on proteins referred to as "natural hotspots," today announced it will present additional preclinical data from the Company's CBL-B program in a poster presentation at the 2023 Society for Immunotherapy of Cancer (SITC) Annual Meeting, taking place November 1-5, 2023, in San Diego, CA. Presentation details are as follows: Title: Exploring Proximal Biomarkers of CBL-B Inhibition in Human Peripheral Blood Mononuclear Cells Session Date and Time: Fri., Nov. 3, 9:00 AM-7:00 PM PT Location: Exhibit Halls A and B1, San Diego Convention Center Abstract Number: 55 About HST-1011 HST-1011 is an investigational orally bioavailable, selective, small molecule allosteric inhibitor of CBL-B, an E3 ubiquitin protein ligase critically involved in immune cell response. Because CBL-B functions as a master regulator of effector cell (T cell and natural killer cell) immunity, its inactivation removes its endogenous negative regulatory functions to substantially enhance anti-tumor immunity. Preclinical data has demonstrated HST-1011's ability to bind to and inhibit a natural hotspot on CBL-B, yielding the activation and propagation of a targeted anti-tumor immune response. Enabled by HotSpot's proprietary Smart Allostery™ platform, HST-1011 is designed with tight binding, low nanomolar potency, a slow dissociation rate from the target to enable sustained pharmacology, and greater selectivity for CBL-B relative to C-CBL. About HotSpot Therapeutics, Inc. HotSpot Therapeutics, Inc. is pioneering a new class of allosteric drugs that target certain naturally occurring pockets on proteins called "natural hotspots." These pockets are decisive in controlling a protein's cellular function and have significant potential for new drug discovery by enabling the systematic design of potent and selective small molecules with novel pharmacology. The Company's proprietary Smart Allostery™ platform combines computational approaches and AI-driven data mining of large and diverse data sets to uncover hotspots with tailored pharmacology toolkits and bespoke chemistry to drive the rapid discovery of novel hotspot-targeted small molecules. Leveraging this approach, HotSpot is building a broad pipeline of novel allosteric therapies for the treatment of cancer and autoimmune diseases. To learn more, visit . Investor & Media Contact: Natalie Wildenradt [email protected] SOURCE HotSpot Therapeutics