PRMT5-MTA inhibitors (Schrödinger)

NEW YORK--( BUSINESS WIRE )--Schrödinger (Nasdaq: SDGR), whose physics-based computational platform is transforming the way therapeutics and materials are discovered, is providing a detailed review of its proprietary drug discovery and development programs during its Pipeline Day today, December 14, from 10:00 a.m. - 12:30 p.m. ET. “We are excited to share our first clinical data for a proprietary Schrödinger program, SGR-1505, and to outline the opportunities emerging from our broad portfolio of drug discovery programs in multiple therapeutic areas, including oncology, immunology and neurology,” stated Karen Akinsanya, Ph.D., president of R&D, therapeutics at Schrödinger. “Our therapeutics team has been very productive since we started building this portfolio. With two programs in the clinic, multiple programs in late discovery and preclinical development, and our advancing collaborations, we believe the future of our therapeutics portfolio is very promising.” SGR-1505 Clinical Progress and Program Update During Pipeline Day, Schrödinger is presenting new data showing that its novel MALT1 inhibitor, SGR-1505, was well tolerated in a Phase 1 study of 73 healthy volunteers. No drug-related serious adverse events or dose limiting toxicities were observed in the study. In the study, SGR-1505 achieved greater than 90 percent inhibition of IL-2 secretion in activated T cells, confirming target engagement and meeting the pharmacodynamic goals for the study. The data support continued evaluation of SGR-1505 in the ongoing Phase 1 study in patients with relapsed or refractory B-cell malignancies. “The data presented from our successful healthy volunteer study demonstrate that SGR-1505 is well-tolerated with a pharmacokinetic and pharmacodynamic profile that supports continued development,” stated Margaret Dugan, M.D., chief medical officer at Schrödinger. “These data add significantly to our understanding of SGR-1505 and inform our clinical development strategy in hematologic malignancies. The SGR-1505 program is progressing well, and we look forward to continued enrollment in the patient study and reporting initial data in late 2024 or 2025.” Schrödinger is also presenting preclinical data for SGR-1505 demonstrating that SGR-1505 has favorable attributes and the potential for combination activity with standard-of-care agents in B cell malignancies. These data were presented earlier this week at the American Society of Hematology Annual Meeting. Three New Programs: EGFR C797S , PRMT5-MTA and NLRP3 Schrödinger is presenting three new proprietary discovery programs at Pipeline Day, targeting EGFR C797S , PRMT5-MTA and NLRP3. EGFR inhibitors are first-line standard of care agents for advanced non-small cell lung cancer patients with activating EGFR mutations, but relapse often occurs due to the development of resistance mutations, including EGFR C797S . Schrödinger has identified multiple EGFR C797S inhibitors and is advancing wild-type sparing, double mutant CNS-penetrant inhibitors with the potential to address brain metastases in patients whose disease progresses following first-line treatment, and to potentially achieve deeper, more durable responses through new combination regimens. PRMT5-MTA inhibition has demonstrated clinical responses in both hematologic and solid tumors with improved safety versus PRMT5 inhibitors due to a synthetic lethal targeting of cancer cells with MTAP-deletions. Schrödinger has identified selective, potent PRMT5-MTA inhibitors with potential applications in solid tumors, brain metastases and primary CNS tumors. NLRP3 is a validated target, and mutations in the NLRP3 gene are associated with a broad spectrum of inflammatory and auto-immune diseases. Schrödinger has identified structurally distinct, selective, NLRP3 inhibitors with anti-inflammatory activity in preclinical models, and is continuing to optimize peripheral and brain-penetrant leads. Broad Portfolio Addresses Synthetic Lethality and DNA-Damage Repair Schrödinger is advancing multiple oncology programs designed to exploit the intrinsic vulnerabilities of cancer cells through synthetic lethality and inhibition of DNA-damage repair. Today, the company is discussing its synthetic lethality programs, PRMT5-MTA and SGR-3515 (Wee1/Myt1). The company is also reviewing SGR-2921, which targets CDC7, a key regulator of replication stress and DNA-damage repair. Schrödinger is reporting preclinical data showing that SGR-3515 has a differentiated biochemical, biophysical and functional profile, with sustained inhibition of Wee1 and Myt1 in tumor cells. Concurrent loss of function of Wee1 and Myt1 confers selective vulnerability in cancer cells and could offer increased anti-tumor activity. SGR-3515 has potential to treat a broad range of solid tumors, including uterine and ovarian cancers. Schrödinger plans to submit an IND for SGR-3515 in the first half of 2024. Schrödinger is also discussing preclinical data presented at ASH demonstrating that SGR-2921 exhibited better activity compared to other CDC7 inhibitors, and showed anti-proliferative effects in treatment-resistant acute myeloid leukemia (AML) patient-derived samples, as well as reduction of blasts in multiple AML models. A Phase 1 study of SGR-2921 is ongoing in patients with AML or myelodysplastic syndrome, and the company expects to report initial data from the study in late 2024 or 2025. “CDC7 is a promising therapeutic target for the treatment of myelodysplastic syndromes and acute myeloid leukemia, diseases for which there is a significant unmet need in treating both frontline and relapsed/refractory patients,” stated Elie Traer, M.D., Ph.D., associate professor at the Center for Hematologic Malignancies at Oregon Health & Science University. “Targeting CDC7 with emerging investigational therapeutics, such as SGR-2921, represents an opportunity to expand our armamentarium of treatment options beyond existing targeted therapies.” Anticipated Milestones Today, Schrödinger outlined the anticipated milestones for its proprietary pipeline: Report initial data from the Phase 1 study of SGR-1505 in late 2024 or 2025 Report initial data from the Phase 1 study of SGR-2921 in late 2024 or 2025 Submit IND for SGR-3515 in the first half of 2024 and initiate a Phase 1 study in 2024 Submit an IND from its discovery portfolio in 2025 Event Information Schrödinger’s Pipeline Day will begin at 10:00 a.m. ET and is expected to conclude at approximately 12:30 p.m. ET. The live presentation can be accessed in the “Investors” section of Schrödinger’s website and will be archived for approximately 90 days. To participate in the live webcast, please register for the event here . It is recommended that participants register at least 15 minutes in advance of the event. About Schrödinger Schrödinger is transforming the way therapeutics and materials are discovered. Schrödinger has pioneered a physics-based computational platform that enables discovery of high-quality, novel molecules for drug development and materials applications more rapidly and at lower cost compared to traditional methods. The software platform is licensed by biopharmaceutical and industrial companies, academic institutions, and government laboratories around the world. Schrödinger’s multidisciplinary drug discovery team also leverages the software platform to advance a portfolio of collaborative and proprietary programs to address unmet medical needs. Founded in 1990, Schrödinger has more than 800 employees and is engaged with customers and collaborators in more than 70 countries. To learn more, visit www.schrodinger.com , follow us on LinkedIn and Instagram , or visit our blog, Extrapolations.com . Cautionary Note Regarding Forward-Looking Statements This press release contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995 including, but not limited to those statements regarding the potential advantages of Schrödinger’s computational platform, the clinical potential and favorable properties of its product candidates, including SGR-1505, SGR-2921 and SGR-3515, the potential for SGR-1505 to be used for the treatment of advanced B-cell malignancies, the potential for SGR-2921 to be used for the treatment of AML or myelodysplastic syndrome, the ability to identify any new product candidates, including from the company’s newly announced drug discovery programs, the timing, progress, and results of clinical trials for its product candidates, and the expected timing of additional IND submissions to the FDA for any product candidates the company identifies. Statements including words such as “aim,” “anticipate,” “believe,” “contemplate,” “continue,” “could,” “estimate,” “expect,” “goal,” “intend,” “may,” “might,” “plan,” “potential,” “predict,” “project,” “should,” “target,” “will,” “would” and statements in the future tense are forward-looking statements. These forward-looking statements reflect Schrödinger’s current views about its plans, intentions, expectations, strategies and prospects, which are based on the information currently available to the company and on assumptions the company has made. Actual results may differ materially from those described in these forward-looking statements and are subject to a variety of assumptions, uncertainties, risks and important factors that are beyond Schrödinger’s control, including the uncertainties inherent in drug development and commercialization, such as the conduct of research activities and the timing of and its ability to initiate and complete preclinical studies and clinical trials, whether results from preclinical and clinical studies will be predictive of the results of later preclinical studies and clinical trials, uncertainties associated with the regulatory review of clinical trials and applications for marketing approvals and the ability to retain and hire key personnel on its business and other risks detailed under the caption “Risk Factors” and elsewhere in the company’s Securities and Exchange Commission filings and reports, including its Quarterly Report on Form 10-Q for the fiscal quarter ended September 30, 2023, filed with the Securities and Exchange Commission on November 1, 2023, as well as future filings and reports by the company. Any forward-looking statements contained in this press release speak only as of the date hereof. Except as required by law, Schrödinger undertakes no duty or obligation to update any forward-looking statements contained in this press release as a result of new information, future events, changes in expectations or otherwise.

SHANGHAI, Oct. 16, 2023 /PRNewswire/ -- Abbisko Therapeutics Co., Ltd. ("Abbisko" hereafter) announced that the results of the company's two preclinical studies published at the 35th International Molecular Targets and Cancer Treatment Conference (EORTC) be held in Boston, U.S.. These two research results respectively demonstrate the latest preclinical research progress of the next generation of PRMT5*MTA inhibitors and small molecule brain penetrant PD-L1 inhibitors in Abbisko's pipeline. As the world's highest-quality research conference focusing on molecular targeting and tumor treatment, the ENA conference collects the most cutting-edge researches on innovative drugs and therapies in the field of tumor treatment. Abbisko presented the following posters at the ENA conference: Title: Discovery and characterization of an MTA-cooperative and brain-penetrant PRMT5 inhibitor Poster number: C130 Session date and time: Saturday, October 14 | 12:30 pm-4:00 pm Session location: Level 2, Exhibit Hall D Background: MTAP is homozygous deleted in ~50% in glioblastoma and many other cancers. PRMT5*MTA inhibition has been shown to be synthetic lethal with MTAP deletion. First generation PRMT5 inhibitors could not distinguish between PRMT5*MTA or PRMT5 alone, thus limited by their shallow therapeutic windows in clinical use. Development of selective PRMT5*MTA inhibitors may improve not only safety but also therapeutic efficacy. Leveraging advanced computation-aided structural analysis and medicinal chemistry design, we have discovered a potent and selective MTA-cooperative and brain-penetrable PRMT5 inhibitor ABK-PRMT5-1, which demonstrates strong anti-tumor activity and brain-penetrating activity in various preclinical models. Conclusion： ABSK-PRMT5-1 strongly inhibits cell proliferation in MTAP-deleted cancer cell lines, with minimal effects on MTAP wildtype cell lines. Furthermore, it significantly reduces SDMA in MTAP-deleted cancer cell lines. Oral administration of ABSK-PRMT5-1 strongly inhibits tumor growth in MTAP-deleted xenograft tumor models. In addition, ABSK-PRMT5-1 demonstrates strong brain penetration with excellent Kp values in animals. DMPK and safety profiling shows good overall drug-like properties of ABK-PRMT5-1. ABK-PRMT5-1, presented here by Abbisko Therapeutics, is a highly selective MTA-cooperative and brain-penetrable PRMT5 inhibitor. Its superior pro fast-track preclinical development. Title: Discovery and characterization of a novel small molecule brain penetrant PD-L1 inhibitor Poster number : B151 Session date and time: Friday, October 13 | 12:30 pm-4:00 pm Session location: Level 2, Exhibit Hall D Background: Immunotherapy has revolutionized cancer treatment in the last decade. Several monoclonal PD-1 and PD-L1 antibodies have been approved for treating various cancers. Small molecule PD-L1 inhibitors with brain-penetrating ability may have potential to overcome the limitations of antibodies and bring benefit for patients with intracranial tumors. Leveraging advanced computation-aided structural analysis and medicinal chemistry design, we have successfully discovered an innovative orally available small molecule PD-L1 inhibitor ABSK044. In preclinical experiments, this compound demonstrates robust T-cell activating ability, strong anti-tumor efficacy, and brain-penetrating activity. Conclusion： ABSK044 strongly inhibits PD-1-PD-L1 interaction with an IC50 less than 1nM in vitro and very potently rescues PD-L1-induced suppression of T cell activation signaling in cells. Furthermore, it efficiently rescues cytokine production in CD8+ T cells suppressed by PD-L1, reaching a level comparable to that of PD-L1 antibodies. In in vivo studies, oral administration of ABSK044 strongly inhibits tumor growth to an extent similar to therapeutic anti-PD-L1 antibodies. Notably, ABSK044 demonstrates excellent brain penetration with a Kp value exceeding 0.4. DMPK and safety profiling demonstrate excellent drug-like properties of ABSK044. ABSK044, presented here by Abbisko Therapeutics, is a highly potent and orally available small molecule PD-L1 antagonist with brain-penetrating activity. Its superior pro its fast-track preclinical development. View original content: SOURCE Abbisko Company Codes: HongKong:2256