K36 Therapeutics, Inc.

NSD2（Nuclear receptor-binding SET domain-containing 2）是一种组蛋白赖氨酸甲基转移酶，该家族还包括NSD1和NSD3。NSD2又称MMSET或WHSC1，含有催化组蛋白3赖氨酸36二甲基化（H3K36me2）的SET结构域以及与染色质相互作用的两个脯氨酸-色氨酸-色氨酸-脯氨酸（PWWP）结构域和五个植物同源结构域（PHD）。NSD2的异常表达、体细胞突变或易位可增加H3K36me2水平，从而对表观基因组进行重编程，促进各种类型人类癌症的进展。例如，在新诊断的多发性骨髓瘤患者中，11%-15%的患者发现了导致NSD2过度表达的t(4:14)易位。此外，有报道称野生型NSD2是前列腺癌细胞中的一种强效致癌基因。NSD2促进前列腺癌转移，在癌症标本中明显上调，在转移性抗阉割肿瘤中的表达量最高。另外，在急性淋巴细胞白血病（ALL）和肺腺癌患者中，NSD2催化SET结构域1099位点突变（E1099K）导致NSD2功能增益。研究发现，基因敲除NSD2可降低H3K36me2水平，抑制体内肿瘤生长。因此，NSD2成为人类癌症的潜在治疗靶点。目前已发现了几种针对NSD2 SET结构域（1、2、3）或PWWP1结构域（4、5）的小分子NSD2抑制剂（图1）。然而，这些抑制剂存在活性低或选择性差的问题。尽管K36 Therapeutics公司开发的新型NSD2-SET 抑制剂KTX-1001化合物已进入I期临床试验（2022年，NCT05651932），用于治疗复发和难治性多发性骨髓瘤患者，但其结构和临床前数据尚未公开。此外，靶向其中任何一个结构域都无法同时消除NSD2的甲基转移酶活性和染色质结合功能。图1 代表性NSD2抑制剂结构式最近也有一些NSD2降解剂被报道（图2）。作为一种新的NSD2调节剂，它能够消除NSD2的催化和非催化功能。目前已报道的降解剂具有较低的降解活性，且缺少体内降解活性评价。图2 已报道的NSD2降解剂近日，中国科学院上海有机化学研究所丁克课题组、密歇根大学Arul M. Chinnaiyan课题组以及丽珠集团合作在药物化学领域Top期刊Journal of Medicinal Chemistry 在线发表了研究论文，报道了一种强效、选择性且具有体内降解活性的NSD2 PROTAC降解剂LLC0424（图3）。图3 NSD2 PROTAC降解剂LLC0424结构式该团队报告了利用PROTAC技术发现的新型NSD2降解剂LLC0424。LLC0424能有效降解NSD2蛋白，在急性淋巴细胞白血病（ALL）细胞RPMI-8402中的DC50值为20 nM，Dmax值为96%。机理研究显示，LLC0424能以cereblon和蛋白酶体依赖的方式选择性地诱导NSD2降解。LLC0424还能持续下调H3K36me2，抑制NSD2突变的ALL细胞系的生长。重要的是，静脉注射或腹腔注射LLC0424可在体内有效降解NSD2（见图4）。图4 LLC0424体内降解活性Discovery of LLC0424 as a Potent and Selective in vivo NSD2 PROTAC DegraderLianchao Liu, Abhijit Parolia, Yihan Liu, Caiyun Hou, Tongchen He, Yuanyuan Qiao, Sanjana Eyunni, Jie Luo, Chungen Li, Yongxing Wang, Fengtao Zhou, Weixue Huang, Xiaomei Ren, Zhen Wang*, Arul M. Chinnaiyan*, and Ke Ding*J. Med. Chem. 2024, doi：10.1021/acs.jmedchem.3c01765声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！长按关注本公众号   粉丝群/投稿/授权/广告等请联系公众号助手 觉得本文好看，请点这里↓

BOULDER, Colo., April 09, 2024 (GLOBE NEWSWIRE) -- Enliven Therapeutics, Inc. (Enliven or the Company) (Nasdaq: ELVN), a clinical-stage precision oncology company focused on the discovery and development of next-generation small molecule kinase inhibitors, today announced the appointment of Lori Kunkel, MD, to its Board of Directors. Dr. Kunkel brings more than twenty-five years of experience in oncology and immunology drug development and commercialization to the Board. “Lori has served as scientific advisor to Enliven since its inception, and we are delighted to now welcome her to our Board,” said Sam Kintz, MBA, Enliven’s Co-founder and Chief Executive Officer. “She brings a wealth of experience as a clinician, academic and industry executive, and we look forward to her continued contributions and insights as we advance our two parallel lead product candidates, ELVN-001 and ELVN-002, through the next set of clinical milestones.” Dr. Kunkel is an accomplished industry executive and board member with a track record of success in corporate strategy, clinical development and commercialization, and business development. She currently serves on the Board of Directors of Nurix Therapeutics, Inc., ORIC Pharmaceuticals, Inc., and K36 Therapeutics, Inc. She is also a scientific advisor to several clinical-stage oncology and immunotherapy companies. Previously, Dr. Kunkel was the acting Chief Medical Officer (CMO) and board member of Loxo Oncology, Inc. (acquired by Eli Lilly and Company). She also served as the CMO at Pharmacyclics LLC (acquired by AbbVie) and Proteolix, Inc. (acquired by Onyx Pharmaceuticals). Prior to joining industry, Dr. Kunkel spent ten years in academic medicine and served as a faculty member at the Bone Marrow Transplant Unit in the Division of Hematology/Oncology at the University of California, Los Angeles. She received her medical degree from University of Southern California and her bachelor’s degree in biology from University of California, San Diego. She is board certified in internal medicine and held board certifications in hematology and oncology. “I am honored to transition from my role as a scientific advisor to a member of the Board of Directors,” said Dr. Kunkel. “I have been deeply engaged with the science at Enliven since the beginning, and I am thrilled to now play a more direct role in guiding its strategic direction. With the Company’s upcoming announcement of initial proof-of-concept data from the ongoing Phase 1a trial of ELVN-001, it is an exciting time for the Company.” About Enliven TherapeuticsEnliven Therapeutics is a clinical-stage biopharmaceutical company focused on the discovery and development of small molecule inhibitors to help people with cancer not only live longer, but live better. Enliven aims to address existing and emerging unmet needs with a precision oncology approach that improves survival and enhances overall well-being. Enliven’s discovery process combines deep insights in clinically validated biological targets and differentiated chemistry to design potentially first-in-class or best-in-class therapies. Enliven is based in Boulder, Colorado. Contact: Investorsir@enliventherapeutics.com Mediamedia@enliventherapeutics.com

Poster to be presented Sunday, December 10, 2023 CAMBRIDGE, Mass., Dec. 4, 2023 /PRNewswire/ -- K36 Therapeutics, Inc. ("K36"), a clinical-stage biotech company focused on developing its first-in-class MMSET inhibitor KTX-1001 for t(4;14) multiple myeloma, today announced that its abstract evaluating KTX-1001 in relapsed and refractory multiple myeloma has been accepted for presentation at the 65th American Society of Hematology (ASH) Annual Meeting and Exposition, which will be held December 9-12, 2023, in San Diego, California, and online. Dr. Jesús G. Berdeja, the Director of Multiple Myeloma Research at Tennessee Oncology, will deliver the presentation as part of the Trials in Progress session. "I am delighted to be presenting the trial progress of KTX-1001 in high-risk subsets like translocation t(4;14)," stated Dr. Berdeja. "There still remains an unmet need for new personalized oral therapies to treat multiple myeloma and novel precision therapeutics like KTX-1001 to address the challenges seen in high-risk patients with translocation t(4;14)." "We are seeing significant interest and momentum in our Phase 1 trial, and I would like to thank the patients, investigators and their staff for their commitment to generate important data from our trial," said Terry Connolly, Ph.D., Chief Executive Officer of K36. "KTX-1001 has demonstrated encouraging preclinical activity and a favorable tolerability profile establishing the potential to create a breakthrough therapy for multiple myeloma patients who have exhausted available standard of care treatments." Presentation Details: Title: Trial in Progress: A Phase 1 Study of KTX-1001, an Oral, First-in-Class, Selective MMSET Inhibitor in Patients with Relapsed and Refractory Multiple Myeloma Poster Number: 3391 Session Name: 653. Multiple Myeloma: Prospective Therapeutic Trials: Poster II Date: Sunday, December 10, 2023 Time: 6:00 PM - 8:00 PM PT Location: San Diego Convention Center, Halls G-H Full abstracts can be found at the ASH Annual Meeting website at . About KTX-1001 KTX-1001 is a novel, first-in-class, potent, and selective methyltransferase inhibitor of the catalytic activity of lysine H3K36. It is an orally administered small molecule being developed initially for the treatment of relapsed and refractory multiple myeloma, with a focus on patients with the t(4;14) translocation. This inhibitor offers a promising avenue for addressing this challenging high risk patient population. About the KTX-1001 Phase 1 Clinical Trial The Phase 1 clinical trial is a single-arm, open-label study in subjects with relapsed and refractory multiple myeloma. It is a multi-part clinical trial with dose escalation followed by an expansion cohort in patients with the genetic translocation t(4;14) to evaluate the safety, tolerability, and preliminary efficacy of different doses of KTX-1001. For more information and participating centers visit NCT05651932. About K36 Therapeutics, Inc. Founded in February 2021, K36 is a privately held biotech company backed by Atlas Venture, F-Prime Capital, Eight Roads Capital, Nextech and Bristol Myers Squibb (NYSE:BMS). Our mission is to translate epigenetic modulation of oncogenic pathways into first-in-class small molecule therapeutics for the benefit of cancer patients worldwide. For more information, please visit and follow us on LinkedIn. SOURCE K36 Therapeutics