Seclidemstat mesylate

近日，郑州大学余斌/宋宜辉在国际权威药物化学期刊《Journal of Medicinal Chemistry》上发表了一篇题为“揭示LSD1的新型结合位点及其变构调节机制以助力新型治疗药物研发”的研究论文。该研究通过深入探索赖氨酸特异性去甲基化酶1（LSD1）的新型结合位点和变构调节机制，为开发新一代LSD1抑制剂提供了重要的结构基础和理论支持。一分钟速览研究背景赖氨酸特异性去甲基化酶1（LSD1）是一种关键的表观遗传调控因子，通过去甲基化功能和非酶功能参与多种细胞过程和基因表达调控。LSD1在多种疾病中发挥重要作用，包括急性髓系白血病、小细胞肺癌、尤因肉瘤、阿尔茨海默病和镰状细胞贫血等。尽管已有多种LSD1抑制剂进入临床试验，但现有的抑制剂主要针对其去甲基化功能，存在药物抗性、非靶向效应以及无法完全调节LSD1非酶功能等问题，限制了其临床疗效。因此，开发能够同时调节LSD1酶活性和非酶功能的新型抑制剂具有重要的临床意义。重点内容本研究聚焦于一种新型变构抑制剂SP2509，通过结合分子动力学模拟和生化实验验证，揭示了SP2509与LSD1的两种新结合模式。这些结合模式能够改变LSD1底物结合口袋的构象，阻断H3底物的结合，从而抑制LSD1的去甲基化活性。研究发现，SP2509的一种结合模式（min0）能够通过变构效应显著影响LSD1的Tower/CoREST结构域，使其发生弯曲，这一效应在以往的实验和计算研究中未曾报道。通过生化实验验证，研究团队进一步确认了SP2509在min0结合位点的变构调节机制，发现E379A突变显著降低了SP2509的抑制活性，而K359A突变影响较小。这表明E379与SP2509之间的卤键比K359与SP2509之间的静电相互作用更强且更稳定。研究总结本研究通过分子动力学模拟和生化实验相结合的方法，揭示了LSD1的新型结合位点和变构调节机制。SP2509作为一种新型变构抑制剂，能够通过改变LSD1的构象来抑制其去甲基化活性和非酶功能。研究结果不仅为设计能够同时调节LSD1酶活性和非酶功能的新型抑制剂提供了宝贵的结构信息，也为开发针对多种疾病的创新疗法奠定了理论基础。图片来源：ACS详细阅读01Background研究背景赖氨酸特异性去甲基化酶1（LSD1）作为一种关键的表观遗传调控因子，自2004年被发现以来，其在染色质修饰复合物的组装和转录因子网络中发挥着重要作用。LSD1通过其经典的去甲基化活性，调节组蛋白和非组蛋白的功能，进而影响基因表达和细胞过程。此外，LSD1还通过与多种蛋白的相互作用发挥非酶功能，这些相互作用使其能够调节多种细胞生物学过程。针对LSD1的抑制剂在治疗多种疾病（包括癌症和神经退行性疾病）中展现出潜在的治疗价值，但现有的临床阶段抑制剂主要靶向其去甲基化功能，存在药物抗性、潜在的非靶向效应、安全性问题以及无法完全调节LSD1的非酶功能等挑战，限制了其治疗效果。因此，开发能够同时调节LSD1去甲基化和非酶功能的新型抑制剂具有重要意义。变构抑制剂SP2509能够抑制LSD1的去甲基化和非酶功能，展现出治疗潜力，但其结合模式尚未明确。本研究旨在通过揭示SP2509的分子结合模式和机制，为设计新一代LSD1抑制剂提供结构基础。02Drug Design药物设计①通过漏斗元动力学（funnel metadynamics，FM）模拟来研究SP2509与LSD1的结合模式通过计算所有结合状态的结合自由能，作者识别出SP2509与LSD1的最优结合模式。模拟结果显示，SP2509在FM模拟中采样的空间（用橙色区域表示）表明其在结合口袋中不断探索结合和未结合区域。结合自由能随模拟时间稳定，表明模拟结果收敛。通过分析一维（1D）和二维（2D）自由能表面（FES），作者发现SP2509存在两种可能的最优结合模式，分别位于1.7 nm和2.3 nm的势能最低点，且这两种模式的势能均接近0 kcal/mol。此外，通过分析SP2509与LSD1之间的关键相互作用，特别是氯原子与LSD1中K359的质子化氮原子之间的静电相互作用，作者进一步定义了另一个集体变量（CV2）。最终，通过二维BFES分析，识别出三个能量低于1 kcal/mol的结合模式，这些模式均表现出SP2509的氯原子与LSD1中K359的稳定相互作用。这些结果为理解SP2509的结合机制提供了重要的结构信息，并为进一步的实验验证和药物设计奠定了基础。图片来源：ACS②最优结合模式基于当前最先进的力场精度，作者认为势能均值低于1 kcal/mol的构象被认为是等能的，并且构成了最优结合状态。通过对每个最优结合态的所有帧进行分析，定义了代表性结合模式，选择标准是包含该状态下最频繁出现的关键相互作用，并尽可能多地包含总体关键相互作用。具体而言，三个结合模式（min0、min1和min2）分别具有2、1和3个频率超过60%的关键相互作用。这些关键相互作用主要涉及SP2509中的氯原子，通过与LSD1中K359或K372的质子化氮原子的静电相互作用，或与E376或E379的负电氧原子的卤键相互作用。这些发现突显了SP2509中大多数原子的显著灵活性。此外，min0和min1结合模式的结合位点和关键相互作用相似，而min2结合模式则明显不同。这些详细的结合模式分析为理解SP2509如何通过不同的结合方式影响LSD1的构象和功能提供了重要的结构基础。图片来源：ACS③无偏分子动力学（MD）模拟来验证和分析SP2509与LSD1复合物的结合模式稳定性通过对LSD1及其配体的Cα原子和非氢原子的均方根偏差（RMSD）分析，结果显示在所有模拟状态下，复合物在最后300纳秒内达到了平衡状态，表现出稳定的构象波动。与CC-90011相比，SP2509和SP2577在两个结合位点（分别称为SP2509/SP2577 min0和SP2509/SP2577 min2）的稳定性较低。为了探究SP2509和SP2577的结合模式在无偏MD模拟过程中是否发生变化，作者计算了用于重建二维自由能表面（BFES）的两个距离（CV1和CV2）的时间演化。结果表明，只有在与SP2509 min0和SP2577 min0复合的LSD1中，CV2偶尔显示出显著偏差。结构分析发现，这些CV2的偏差是由于K359侧链的柔性导致的，其构象间歇性地从指向SP2509转变为指向溶剂，类似于在晶体结构中观察到的构象。这些发现表明，通过FM模拟识别的主要结合模式在无偏MD模拟过程中保持稳定。图片来源：ACS03In vitro In Vivo体内外评价①SP2509是LSD1/CoREST复合物中Tower结构域的变构调节剂作者通过主成分分析（PCA）比较了LSD1在不同结合条件下的构象状态，包括apo形式、与SP2509结合以及与两种临床试验抑制剂（SP2577和CC-90011）结合的情况。研究发现，CoREST的结合显著影响了LSD1的构象，使其在没有CoREST时表现出更广泛的PC1值分布，而CoREST结合则将其限制在一个更狭窄且一致的范围内，且这种影响与配体类型或结合位点无关。有趣的是，SP2509 min0结合（包括SP2509 min0和SP2509 min0-fixed）进一步将PC1分布限制在更小的值，表明其对LSD1具有独特的调节作用。结构分析显示，PC1代表了Tower结构域相对于Sα1螺旋片段（残基373-395）的垂直运动，而PC2描述了Tower结构域沿Sα1螺旋的运动。CoREST的结合使LSD1的Tower结构域呈现出更直立的构象，这对于CoREST与组蛋白和DNA组分在LSD1核小体底物中的相互作用至关重要。除了SP2509 min0结合外，其他配体的结合并未显著改变这一状态。SP2509 min0和SP2509 min0-fixed结合均导致Tower/CoREST区域弯曲，表明这种效应并非偶然。然而，另一个LSD1与SP2509 min0结合的模拟轨迹（称为SP2509 min0-parallel）并未表现出这种独特效应。这些结果表明，SP2509作为一种变构调节剂，能够通过影响Tower结构域的构象来调节LSD1的功能，这种调节作用可能对LSD1与核小体底物的相互作用产生重要影响。图片来源：ACS②球状结构域的复杂构象动态作者通过主成分分析（PCA）研究了LSD1的球状结构域在不同结合条件下的构象动态。与整体LSD1结构的主要构象动态主要由前两个主成分（PCs）捕获不同，球状结构域的构象动态更为复杂，前两个主成分仅能解释34.3%的累积方差。分析前四个主成分（PC1-4）的分布表明，CoREST、配体类型和结合位点等多种因素共同影响球状结构域的构象变化。此外，通过详细分析LSD1的底物结合口袋沿PC1和PC2的运动，揭示了其复杂且灵活的动态特性。这些发现强调了LSD1底物结合口袋的高度适应性和动态性，这种动态特性难以从X射线晶体学和冷冻电镜等静态结构数据中捕捉到。图片来源：ACS③详细的结合模式诱导Tower/CoREST结构域的变构弯曲作者详细分析了SP2509和SP2577在不同结合位点（min0和min2）上的结合模式，并探讨了这些结合模式如何诱导LSD1的Tower/CoREST结构域发生别构弯曲。研究发现，SP2509在min0结合位点时，其苯酚羟基指向底物结合口袋的内部，导致配体与Sα1区域的距离较远，从而形成了一个较大的结合口袋。这种独特的口袋形状使得Tower/CoREST结构域能够发生弯曲。相比之下，SP2509在min0-parallel结合模式以及SP2577在min0结合模式下，苯酚羟基指向外部，导致结合口袋变小，不利于Tower/CoREST结构域的弯曲。此外，作者通过主成分分析（PCA）进一步确认了结合口袋的形状（而非特定残基）是影响Tower/CoREST结构域弯曲的关键因素。这些结果表明，SP2509的结合模式能够通过改变结合口袋的形状，诱导LSD1的Tower/CoREST结构域发生变构弯曲，从而可能影响其与核小体底物的相互作用。图片来源：ACS④生化实验验证了SP2509与LSD1在min0结合位点的变构结合模式研究发现，E379和K359在所有min0结合配置中均参与了关键相互作用，表明它们在SP2509介导的别构调节中起着至关重要的作用。为了验证这一点，作者测试了E379A和K359A突变对LSD1与H3K4me2底物结合亲和力的影响，以及对SP2509抑制活性的影响。结果显示，E379A突变显著降低了LSD1对H3K4me2的结合亲和力（KM值显著增加），同时也降低了SP2509对LSD1/CoREST复合物的抑制活性（IC50和Ki值显著增加）。相比之下，K359A突变对SP2509的抑制活性影响较小。这些结果表明，E379与SP2509之间的卤键比K359与SP2509之间的静电相互作用更强且更稳定。这些发现进一步证实了SP2509在min0结合位点的别构调节机制，并为设计针对LSD1的新型抑制剂提供了重要的结构基础。图片来源：ACS总结目前处于临床阶段的LSD1抑制剂主要靶向其去甲基化功能，而靶向LSD1的非酶功能的抑制剂仍处于初级阶段。SP2509作为一种代表性的变构抑制剂，能够同时抑制LSD1的酶活性和非酶功能，因此对于探究抑制机制具有重要价值。通过广泛的漏斗元动力学（FM）和无偏分子动力学（MD）模拟，本研究揭示了SP2509在LSD1上的两个新的结合位点，这些结合位点能够诱导底物结合口袋入口处的构象变化，从而阻碍H3底物的结合并抑制LSD1的去甲基化活性。特别值得注意的是，SP2509在“min0”结合位点的结合能够对Tower/CoREST结构域产生别构效应，导致该结构域显著弯曲，这可能干扰LSD1/CoREST与核小体底物的相互作用。此外，生化实验验证了SP2509在min0结合位点的别构调节机制，突变分析表明E379A突变显著降低了SP2509的抑制活性，而K359A突变影响较小。这些结果表明E379与SP2509之间的卤键比K359与SP2509之间的相互作用更强且更稳定。综上所述，这些发现为设计能够同时靶向LSD1的酶活性和非酶功能的新一代抑制剂提供了结构基础，并可能推动针对多种疾病的新型疗法的开发。参考来源：https://doi.org/10.1021/acs.jmedchem.5c00966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↓

Decoy’s development of novel peptide-conjugate therapeutics arising from its proprietary IMP3ACT™ platform to benefit from Dr. Langer’s extensive scientific knowledge and experienceCAMBRIDGE, Mass. and HOUSTON, April 16, 2025 (GLOBE NEWSWIRE) -- Decoy Therapeutics, Inc. (Decoy), a privately held preclinical biopharmaceutical company engineering the next generation of peptide conjugate therapeutics, announces that Massachusetts Institute of Technology (MIT) Professor and Moderna co-founder Robert S. Langer, ScD will join the company’s Scientific Advisory Board (SAB) upon the successful completion of Decoy’s merger with Salarius Pharmaceuticals, Inc. (NASDAQ: SLRX). As announced on January 13, 2025, Decoy and Salarius Pharmaceuticals signed a definitive agreement under which Decoy Therapeutics will merge with a wholly owned subsidiary of Salarius Pharmaceuticals, with the newly formed company to be named Decoy Therapeutics. Dr. Langer is a world-renowned scientist, entrepreneur and biotechnology visionary. His groundbreaking work in drug delivery systems design and in tissue engineering have earned him numerous awards, including the prestigious National Medal of Science and the Charles Stark Draper Prize. Drug development technologies that Dr. Langer pioneered have laid the foundations for transformative medicines including Roche’s cancer drug bevacizumab (Avastin®) and Moderna's Spikevax® mRNA Covid vaccine. "It’s an honor to have Dr. Langer join our SAB,” commented Michael M. Lipp, PhD, Chief Technology Officer of Decoy. “Having worked in Dr. Langer’s lab and at start-up companies that were founded on innovations arising from his lab, I’ve seen first-hand the impact he brings in discovering transformational therapies and advancing their development. We are confident that Dr. Langer’s tremendous experience and know-how will provide invaluable support as we use our proprietary IMP3ACT platform to advance a portfolio of proprietary peptide-conjugate products.” “Decoy is utilizing an innovative, next-generation peptide-conjugate platform to discover and develop much-needed and differentiated antiviral and cancer therapies,” said Dr. Langer. “I am excited to collaborate with the Decoy team and to lend my expertise to expedite the development of these potentially high-impact therapeutics.” “We are thrilled Dr. Langer has agreed to join our SAB thus expanding our thought leadership,” added Shahin Gharakhanian, MD, acting Chief Medical Officer and SAB Chair of Decoy. “We look forward to synergizing his guidance with our current SAB members and incorporating his drug design perspectives, particularly calling upon his expertise in developing dosage forms and routes of administration for Decoy’s peptide-conjugate drugs.” Dr. Langer is one of nine Institute Professors at MIT, the institution’s highest faculty honor, and is a faculty member of the Harvard-MIT program in Health Sciences and Technology. His pioneering work has benefited millions of people worldwide and includes isolating the first angiogenesis inhibitors (with Dr. Judah Folkman) leading to new treatments for cancer and blindness. He also created the first nanoparticles and microparticles for delivering large molecules including nucleic acids, and helped establish the field of tissue engineering, which enabled artificial skin for burn victims and organ-on-a-chip technology. Dr. Langer has authored more than 1,600 scientific papers with more than 444,000 citations, making him the most-cited biological engineer in history. His patents have been licensed or sublicensed to over 400 companies and he has co-founded more than 40 ventures. Dr. Langer chaired the FDA’s Science Board from 1999–2002. He has received more than 220 awards and is one of only three living individuals to receive both the U.S. National Medal of Science and the National Medal of Technology and Innovation. His accolades include the Draper Prize, the Queen Elizabeth Prize for Engineering, the Albany Medical Center Prize, the Breakthrough Prize in Life Sciences, the Kyoto Prize, the Wolf Prize in Chemistry, the Millennium Technology Prize and the Kavli Prize in Nanoscience. He holds 44 honorary doctorates from institutions including Harvard University, Yale University, Columbia University and the University of Oxford, and has been elected to the National Academies of Medicine, Engineering and Sciences, as well as the National Academy of Inventors. About Decoy’s Peptide Conjugate Technology Decoy’s drug design engine uses the power of computational tools and fast peptide synthesis technology pioneered in the laboratory of Brad Pentelute, Ph.D., Professor of Chemistry at MIT and Decoy co-founder, to rapidly engineer and synthesize novel antivirals that directly target highly conserved viral machinery. Its proprietary IMP3ACT peptide conjugate drug design and manufacturing platform leverages machine learning and artificial intelligence (AI) tools. IMP3ACT allows for the rapid computational design and manufacturing of innovative peptide-conjugate therapeutics including rapid response to novel viral pathogens including H5N1 avian flu. Peptide conjugates are a new class of drug, perhaps best known for the popular diabetes and weight loss medications, that takes advantage of the strong activity and selectivity of peptides, and improves their targeting and durability by adding a lipid molecule. Decoy Therapeutics is expanding the use of this new drug class to indications including infectious diseases and cancer. The IMP3ACT platform leverages peptide chemistry to design a-helical peptides using computational and machine learning tools. These peptides are transformed into multimeric conjugates by chemically linking a defined number of copies to lipids or other suitable membrane anchor moieties, enhancing their drug-like properties and dosing flexibility with extended pharmacokinetics. Decoy’s technology has produced peptide conjugates effective in vitro against multiple human coronaviruses, including all SARS-CoV-2 major variants of concern to date, and against RSV A, RSV B and hPIV3, and in vivo against the SARS-CoV-2 delta variant. By integrating machine learning algorithms in peptide design and synthesis, Decoy’s platform accelerates the creation of lead molecules for preclinical evaluations, simultaneously optimizing peptide conjugates for enhanced affinity, binding specificity, resistance to proteases, pharmacokinetic properties and manufacturability at early commercial scale. About Decoy Therapeutics, Inc. Decoy Therapeutics is a preclinical-stage biotechnology company that is leveraging machine learning and artificial intelligence tools alongside high-speed synthesis techniques to rapidly design, engineer and manufacture peptide-conjugate drug candidates that target serious unmet medical needs. The company’s initial pipeline is focused on respiratory viruses and GI cancers. Decoy has attracted financing from institutional investors as well as significant non-dilutive capital from the Massachusetts Life Sciences Seed Fund, the Google AI startup program and the NVIDIA Inception program among other sources. The company has also received QuickFire Challenge award funding provided by the Biomedical Advanced Research and Development Authority (BARDA) through BLUE KNIGHT™, a collaboration between Johnson & Johnson Innovation – JLABS and BARDA within the Administration for Strategic Preparedness and Response. For more information, please visit www.DecoyTx.com. About Salarius Pharmaceuticals, Inc. Salarius Pharmaceuticals is a clinical-stage biopharmaceutical company with two drug candidates for patients with cancer in need of new treatment options. Salarius’ product portfolio includes seclidemstat, the company’s lead candidate, which is being studied in an investigator-initiated Phase 1/2 clinical study in hematologic cancers underway at MD Anderson Cancer Center as a potential treatment for MDS and CMML in patients with limited treatment options. SP-3164, the company’s IND-stage second asset, is an oral small molecule protein degrader. Salarius previously received financial support for seclidemstat for the treatment of Ewing sarcoma from the National Pediatric Cancer Foundation and was a recipient of a Product Development Award from the Cancer Prevention and Research Institute of Texas (CPRIT). For more information, please visit www.salariuspharma.com. About the Proposed Transaction Definitive agreements were executed with unanimous approvals by the Boards of Directors of Salarius and Decoy. The closing consideration will consist primarily of nonvoting preferred stock of Salarius, and it is expected that following closing and a post-closing stockholder vote to approve the conversion of the preferred shares into common stock, Decoy investors would own approximately 86% of the outstanding shares of the merged company and Salarius stockholders would own approximately 14% of the outstanding shares, in each case exclusive of any shares issued in any financing, including the qualifying financing(s) necessary to consummate the merger transaction. For further details on the transaction and conditions for closing of the merger, please refer to the Form 8-Ks Salarius filed with the U.S. Securities and Exchange Commission (SEC) on each of January 13, 2025 and March 8, 2025 at www.sec.gov. Non-Solicitation This communication shall not constitute an offer to sell or the solicitation of an offer to sell or the solicitation of an offer to buy any securities, nor shall there be any sale of securities in any jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such jurisdiction. No public offer of securities in connection with the merger shall be made except by means of a prospectus meeting the requirements of Section 10 of the Securities Act of 1933, as amended. Forward-Looking Statements This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995 regarding Salarius, Decoy, the proposed merger and other matters, including without limitation, statements relating to plans and expectations relating to the business, scientific advisory board, products, including expected achievement of milestones for its lead asset and future prospects of Decoy and the combined company. These statements may discuss goals, intentions and expectations as to future plans, trends, events, results of operations or financial condition, or otherwise, based on current beliefs of the management of Salarius, as well as assumptions made by, and information currently available to, management. Forward-looking statements generally include statements that are predictive in nature and depend upon or refer to future events or conditions, and include words such as “may,” “will,” “should,” “would,” “expect,” “anticipate,” “plan,” “likely,” “believe,” “estimate,” “project,” “intend,” and other similar expressions. Statements that are not historical facts are forward-looking statements. Forward-looking statements are based on current beliefs and assumptions that are subject to risks and uncertainties and are not guarantees of future performance. Actual results could differ materially from those contained in any forward-looking statement as a result of various factors, including, without limitation: the risk that the conditions to the closing are not satisfied, including uncertainties as to the timing of the consummation of the proposed merger; the ability of each of Salarius and Decoy to consummate the merger; risks related to Salarius’ ability to estimate and manage its operating expenses and its expenses associated with the proposed merger pending the closing; risks that the combined company will not achieve the synergies expected from the proposed merger; risks that Salarius and the combined company will not obtain sufficient financing to execute on their business plans and risks related to Decoy’s products and development plans, including unanticipated issues with any IND application process and the potential of the IMP3ACT™ platform. Readers are urged to carefully review and consider the various disclosures made by Salarius in its reports filed with the SEC, including its Annual Report on Form 10-K for the fiscal year ended December 31, 2024, as revised or supplemented by its Quarterly Reports on Form 10-Q and other documents filed with the SEC. If one or more of these risks or uncertainties materialize, or if the underlying assumptions prove incorrect, Salarius’ actual results may vary materially from those expected or projected. CONTACTS: Decoy Therapeutics, Inc.Rick Pierce, CEOPierce@decoytx.com617-447-8299 Business Development:Peter Marschel, CBOPeter@Decoytx.com617-943-6305 Salarius Pharmaceuticals, Inc.Alliance Advisors IRJody Cainjcain@allianceadvisors.com310-691-7100