Provided herein are novel MALT1 inhibitors, pharmaceutical compositions, use of such compounds in treating cancer and immunological diseases and processes for preparing such compounds.

2024-02-22·Journal of medicinal chemistry1区 · 医学

Development of Potent MALT1 Inhibitors Featuring a Novel “2-Thioxo-2,3-dihydrothiazolo[4,5-d]pyrimidin-7(6H)-one” Scaffold for the Treatment of B Cell Lymphoma

1区 · 医学

Article

作者: Liang, Renwen ; Sun, Chenxia ; Ren, Hairu ; Yang, Chenghua ; Zhao, Jiayan ; Feng, Zhuanghui ; Liang, Xuewu ; Wei, Xiaohui ; Saidahmatov, Abdusaid ; Yu, Haolan ; Liu, Hong

Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) has emerged as a novel and promising therapeutic target for the treatment of lymphomas and autoimmune diseases. Herein, we reported a new class of MALT1 inhibitors featuring a novel "2-thioxo-2,3-dihydrothiazolo[4,5-d]pyrimidin-7(6H)-one" scaffold developed by structure-based drug design. Structure-activity relationship studies finally led to the discovery of MALT1 inhibitor 10m, which covalently and potently inhibited MALT1 protease with the IC₅₀ value of 1.7 μM. 10m demonstrated potent and selective antiproliferative activity against ABC-DLBCL and powerful ability to induce HBL1 apoptosis. 10m also effectively downregulated the activities of MALT1 and its downstream signal pathways. Furthermore, 10m induced upregulation of mTOR and PI3K-Akt signals and exhibited a synergistic antitumor effect with Rapamycin in HBL1 cells. More importantly, 10m remarkably suppressed the tumor growth both in the implanted HBL1 and TMD8 xenograft models. Collectively, this work provides valuable MALT1 inhibitors with a distinct core structure.

2024-01-01·Poultry science

Mucosa-associated lymphoid tissue lymphoma translocation protein 1 inhibition alleviates intestinal impairment induced by chronic heat stress in finisher broilers

Article

作者: Pertiwi, Herinda ; Michiels, Joris ; Zhang, Huaiyong ; Majdeddin, Maryam

Heat stress (HS) in poultry has deleterious effects on intestinal development and barrier function, along with inflammatory outbursts. In the present study, chronic HS reduced body weight of broilers and activated mucosa-associated lymphoid tissue lymphoma translocation protein 1 (Malt1) /nuclear factor kappa B (NF-κB) signaling pathways to elicit the inflammatory cytokine response in jejunum. Subsequently, this study investigated the protective effects of the Malt1 inhibitor on the intestine of broilers under HS conditions. The 21-day-old male broilers were allocated to 8 pens housed in HS room (34°C for 7 h/d) until 28 d of age. During this period, 4 birds were selected from each heat-stressed pen and received intraperitoneal injection of 20 mg/kg body weight Mepazine (a Malt1 inhibitor) or the equivalent volume of phosphate buffer saline (PBS) every other day. When compared to PBS broilers, birds received Mepazine injection exhibited increased relative weight and higher villus height in jejunum (both P < 0.05). Mepazine treatment also increased (P < 0.05) the mRNA of zonula occludens-1 (ZO-1), claudin-1, and cadherin 1 of jejunum, which was companied by the reduced caspase-3 transcription under HS condition. Meanwhile, the gene expression levels of toll-like receptor 4 (TLR4), Malt1, NF-κB, interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α) in the jejunum were significantly downregulated by Mepazine administration (P < 0.05). Although there were no significant differences in the relative weight of the thymus and bursa, the transcription levels of T helper 1 (Th1)- and Th17-related cytokines were lower in thymus of birds injected with Mepazine. The cytokines of Treg cytokine transforming growth factor beta (TGF-β) and forkhead box protein P3 (Foxp3) in both the thymus and bursa were not influenced. These results suggest that inhibition of Malt1 protease activity can protect intestinal integrity by promoting the production of tight junction proteins and attenuating NF-κB-mediated intestinal inflammation response under HS conditions.

项与 MALT1 inhibitors (CD3) 相关的新闻（医药）

2024-03-20

·BioSpace

Schrödinger Highlights Discovery of SGR-1505, Clinical-Stage MALT1 Inhibitor, at American Chemical Society National Meeting

NEW ORLEANS--(BUSINESS WIRE)-- Schrödinger, Inc. (Nasdaq: SDGR), whose physics-based computational platform is transforming the way therapeutics and materials are discovered, today presented the discovery of SGR-1505, its MALT1 inhibitor, during the First Time Disclosure Session at the American Chemical Society (ACS) Spring 2024 Meeting. SGR-1505 is being evaluated in a Phase 1 dose-escalation study in patients with relapsed/refractory B-cell malignancies. The oral presentation provided an overview of how Schrödinger leveraged its computational approaches at scale to discover SGR-1505. Schrödinger’s platform enabled vast exploration of chemical space, triaging 8.2 billion compounds, synthesizing 78 of the most promising molecules in the lead series, and identifying SGR-1505 as the company’s development candidate in approximately 10 months. Reaching a development candidate can take three to six years and typically involves synthesizing up to 5,000 molecules per program. “Designing the optimal molecule is a tremendous multi-parameter optimization challenge that requires balancing many key properties,” stated Aleksey Gerasyuto, Ph.D., head of medicinal chemistry at Schrödinger. “One of our goals in this program was to address the limitations reported with other MALT1 inhibitors. By leveraging our computational platform, our cross-functional team simultaneously and rapidly optimized key drug-like properties and designed several distinct chemical series, ultimately selecting SGR-1505 as our development candidate.” “We believe SGR-1505 has the potential to be a best-in-class compound. The preclinical pro SGR-1505, coupled with positive data from our recently completed Phase 1 study in healthy subjects, further increases our conviction about our MALT1 program,” said Margaret Dugan, M.D., chief medical officer at Schrödinger. “Our Phase 1 study in patients with relapsed/refractory B-cell lymphomas is progressing well, and we look forward to reporting initial data from the study in late 2024 or 2025.” SGR-1505 Clinical Studies Schrödinger is conducting a Phase 1 dose-escalation study in patients with relapsed/refractory B-cell lymphomas to evaluate the safety, pharmacokinetics, pharmacodynamics and preliminary signals of therapeutic activity of SGR-1505 as a monotherapy. The study is enrolling patients at multiple sites in the U.S. and Europe. Once the recommended dose is determined, an expansion cohort is planned to evaluate SGR-1505 in combination with other anti-cancer agents, such as BTK and BCL-2 inhibitors, in patients with specific B-cell malignancies. Schrödinger recently completed a Phase 1 study showing that 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. The data also confirmed target engagement, with greater than 90 percent inhibition of IL-2 secretion in activated T cells, a pharmacodynamic goal of the study. 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 approximately 850 employees and is engaged with customers and collaborators in more than 70 countries. To learn more, visit , 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 regarding the potential advantages of our computational platform, our research and development efforts for SGR-1505, the timing, progress, and results of clinical trials of SGR-1505, the clinical potential and favorable properties of SGR-1505, and the potential for SGR-1505 to be used for the treatment of advanced B-cell lymphomas. 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 our current views about our plans, intentions, expectations, strategies and prospects, which are based on the information currently available to us and on assumptions we have made. Actual results may differ materially from those described in the forward-looking statements and are subject to a variety of assumptions, uncertainties, risks and factors that are beyond our control, including the uncertainties inherent in drug development and commercialization, such as the conduct of research activities and the timing of and our ability to initiate and complete preclinical studies and clinical trials, whether results from preclinical studies and early clinical trials will be predictive of results of later preclinical studies and clinical trials, uncertainties associated with the regulatory review of clinical trials and applications for marketing approvals, the ability to retain and hire key personnel and other risks detailed under the caption "Risk Factors" and elsewhere in our Securities and Exchange Commission filings and reports, including our Annual Report on Form 10-K for the fiscal year ended December 31, 2023, filed with the Securities and Exchange Commission on February 28, 2024, as well as future filings and reports by us. Any forward-looking statements contained in this press release speak only as of the date hereof. Except as required by law, we undertake 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.

临床1期AACR会议

2023-11-02

·PRNewswire

HotSpot Therapeutics to Introduce First-in-Class MALT1 Scaffolding Inhibitor at 65th ASH Annual Meeting

Oral presentation will showcase distinct preclinical profile for potent, selective MALT1 scaffolding inhibitor that is highly differentiated from MALT1 protease inhibitors BOSTON, Nov. 2, 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 preclinical data from the Company's highly differentiated mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) program in an oral presentation at the 2023 American Society of Hemotology (ASH) Annual Meeting, taking place December 9-12, 2023, in San Diego, CA. MALT1 is a component of the CARD11-BCL10-MALT1 (CBM) protein complex, which serves as a key regulator of NFkB signaling in cells, including B and T cells. MALT1 is implicated in a range of hematological malignancies, including Non-Hodgkin's lymphoma, as well as other lymphomas and selected solid tumors. Leveraging our proprietary Smart Allostery™ platform, HotSpot has developed first-in-class small molecules designed to selectively inhibit the scaffolding function of MALT1, a dominant driver of the NFkB pathway. This oral presentation will describe the differentiated preclinical profile for HotSpot's scaffolding inhibitor, including the potential for an improved efficacy and safety profile versus traditional MALT1 inhibitors that target protease function. HotSpot plans to file an IND for HST-1021, its Development Candidate, in 2024. Presentation details are as follows: Title: Discovery of Novel, First-in-Class Allosteric Modulators of MALT1 Scaffolding Function with Differentiated Pharmacology for NFκB-Driven Malignancies Session Name: 605. Molecular Pharmacology and Drug Resistance: Lymphoid Neoplasms: Novel Therapeutic Approaches in Lymphoma and Multiple Myeloma Session Date and Time: Sat., Dec., 9, 2023, 9:30-11:00 AM PT Presentation Time: 10:15 AM PT Location: Manchester Grand Hyatt San Diego, Grand Hall D Publication Number: 52 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

ASH会议

2023-10-16

·BioSpace

Exscientia to Present New Preclinical Data for AI-designed LSD1 and MALT1 Inhibitors at ESMO 2023

— Demonstrated preclinical efficacy of LSD1 inhibitor in primary AML samples — — Initial data supporting combination potential of LSD1 inhibitor with AML standard of care therapies — — Tumour growth inhibition through MALT1 in monotherapy and combination while lowering bilirubin toxicity risk — OXFORD, England--(BUSINESS WIRE)-- Exscientia plc (Nasdaq: EXAI) today announced two abstracts to be presented at the upcoming European Society for Medical Oncology (ESMO) Congress 2023 from October 20-24, 2023 in Madrid, Spain. “We are excited to share new preclinical data on our precision-designed LSD1 and MALT1 inhibitors, which we introduced to our oncology pipeline earlier this year,” said Professor Andrew Hopkins FRS FMedSci, founder and Chief Executive Officer of Exscientia. “We believe these compounds bear strong potential for differentiation, patient benefit and value creation. This data underlines how Exscientia can bring together AI design and novel translational research capabilities to create better quality drug candidates. This also allows us to systematically identify those patient populations who have the most potential benefit well before we start clinical trials.” Both ESMO posters will be available on the Exscientia website from their time of presentation. Poster Presentations Title: Determining anti-cancer efficacy of a reversible LSD1 inhibitor, EXS74539, in primary AML tissues with limited thrombocytopenic effects Session Title: Translational research (agnostic) Abstract Number: 2289P Date/Time: Saturday, October 21 / 12:00 PM – 1:00 PM CEST ‘539 is a novel, potent, selective and reversible LSD1 inhibitor under preclinical investigation as a monotherapy or in combination with standard of care for oncology and haematology indications including acute myeloid leukaemia (AML) and small cell lung cancer (SCLC) Leveraging primary human material and Exscientia’s proprietary precision medicine platform, the Company confirmed ‘539’s general efficacy, demonstrating that ‘539 induces AML cell differentiation marker expression when used on primary AML patient tissue ex vivo Combination data with first line AML and targeted therapies will be presented Title: Characterisation of EXS73565, a potent and selective MALT1 inhibitor with low drug-drug interaction risk and potential in lymphoma Session Title: Haematological malignancies Abstract Number: 832P Date/Time: Monday, October 23 / 12:00 PM – 1:00 PM CEST Exscientia utilised generative design, machine learning and molecular dynamics approaches to precision-design ‘565, a potent and selective allosteric MALT1 inhibitor with a differentiated pro low drug-drug interaction and hyperbilirubinemia risk Preclinically, ‘565 exposure resulted in limited inhibition of UGT1A1, an enzyme involved in bilirubin metabolism. This approach has the potential to offer safety benefits compared to other clinical stage MALT1 inhibitors which carry a high UGT1A1 inhibition and hyperbilirubinemia risk Significant tumour growth inhibition was observed for ‘565 in vivo in activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL) xenograft models. Significant synergistic effects were observed for combination ‘565 and the BTK inhibitor ibrutinib in a xenograft model with low sensitivity to either single agent Overall, the pro ‘565 offers the potential for clinical exploration of MALT1 inhibition as a monotherapy and/or in combination with other targeted agents in haematological malignancies About Exscientia Exscientia is an AI-driven precision medicine company committed to discovering, designing and developing the best possible drugs in the fastest and most effective manner. Exscientia developed the first-ever functional precision oncology platform to successfully guide treatment selection and improve patient outcomes in a prospective interventional clinical study, as well as to progress AI-designed small molecules into the clinical setting. Our internal pipeline is focused on leveraging our precision medicine platform in oncology, while our partnered pipeline broadens our approach to other therapeutic areas. By pioneering a new approach to medicine creation, we believe the best ideas of science can rapidly become the best medicines for patients. Forward-Looking Statements This press release contains certain forward-looking statements within the meaning of the “safe harbor” provisions of the Private Securities Litigation Reform Act of 1995, including statements with regard to Exscientia’s expectations regarding its Board of Directors. Words such as “anticipates,” "believes," “expects,” "intends," "projects," "anticipates," and "future" or similar expressions are intended to identify forward-looking statements. These forward-looking statements are subject to the uncertainties inherent in predicting future results and conditions and no assurance can be given that the drug discovery and precision medicine platforms discussed above will be successful in optimising drug candidates for specific patient populations. The success of Exscientia’s platforms is subject to numerous factors, many of which are beyond the control of Exscientia, including, without limitation, the ability of Exscientia to design clinical trials that are cleared by the FDA and of healthcare providers to collect viable patient tissue samples. Exscientia undertakes no obligation to publicly update or revise any forward-looking statements, whether as a result of new information, future events or otherwise, except as may be required by law. Visit us at or follow us on X/Twitter @exscientiaAI.

100 项与 MALT1 inhibitors (CD3) 相关的药物交易

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