S-64315

DUBLIN--( BUSINESS WIRE )--The "Global MCL1 Inhibitor Drug Clinical Trials & Commercialization Opportunity Insights 2023" report has been added to ResearchAndMarkets.com's offering. A compelling case has been made for the use of MCL-1 inhibitors in the treatment of cancer by the positive preclinical trial results of numerous other investigational candidates besides S63845. MCL-1 also has the potential to be used as a therapeutic target for a variety of malignancies, as evidenced by the outcomes of the expansion of these candidates to solid tumors. Research and development of MCL-1 inhibitors is still an emerging field, however, prominent pharmaceutical companies like Amgen, Novartis, and AstraZeneca have also invested in the development of these candidates, which vouches for the future potential of MCL-1 inhibitors and the unanticipated market growth in the coming years. There still remain certain drawbacks associated with MCL-1 inhibitors that need to be addressed to realize the prospective growth potential of the MCL-1 inhibitors market. MCL-1 has been identified as a central protein in the pathogenesis of several cancers, majorly hematopoietic malignancies. It is a dynamic and unique protein, which is involved in a variety of cellular functions, including cell cycle progression, metabolism, and differentiation among others. However, its role as a pro-survival member of the BCL-2 that prevents apoptosis is what has brought it into the limelight as a promising therapeutic target for cancer. In addition, overexpression of MCL-1 also promoted drug resistance of both solid tumors and hematological malignancies to various chemotherapeutic agents through different signaling mechanisms. Therefore, due to its key role in promoting cell survival and the resistance to treatment, MCL-1 has emerged as a promising therapeutic target, and researchers are now working to find strategies to inhibit MCL-1. Compared to other proteins, targeted inhibition of the MCL-1 has more advantages. The protein is overexpressed in a number of cancers including breast and lung cancers, two cancers having the highest incidence and mortality rates. MCL-1 can prevent the process of apoptosis in cancer cells and promote survival, leading to an increase in tumor mass. In preclinical trials, inhibition of the MCL-1 was shown to induce cell death. Additionally, it also increased the efficacy of other anticancer drugs administered in combination with the MCL-1 inhibitor. Further, MCL-1 is also indicated in the development of resistance to current treatments. Especially in blood cancers, resistance to treatment is a common event occurring in cancer patients and is something that has been challenging the treatment outcomes and survival of patients. Overexpression of MCL-1 plays a role in this as its upregulation can counteract the effects of drugs that induce apoptosis otherwise. Targeting the MCL-1 can overcome this resistance and enhance the effectiveness of chemotherapies used in treating hematopoietic cancers. Adding on to this, the combination of MCL-1 inhibitors with other targeted therapies and anticancer drugs can have a synergic effect on cancer cells, leading to enhanced cell death and improved treatment outcomes. Research has also found that while normal cells rely on several survival mechanisms, most cancer cells become highly dependent on MCL-1 for their survival. Therefore, it is hypothesized that targeting the MCL-1 will be a highly targeted strategy specific to cancer cells, and it will leave non-cancer cells unharmed. To some extent, results from clinical and preclinical trials conducted by researchers and drug developers have been able to justify this. Though there remain some limitations such as the emergence of unforeseen adverse effects such as cardiac problems, the potential of MCL-1 as a therapeutic target cannot be denied, and is an avenue that needs to be explored more with potential candidates. Results from preclinical and clinical trials for many promising candidates have returned encouraging outcomes. S63845 was among the first candidates to enter preclinical trials, and to date, it has been assessed in a number of solid and hematopoietic cancers and has shown promising results. Servier and Novartis jointly developed S64315/MIK665, the clinical-trial version of S63845. As mentioned above, MCL-1 inhibitors can act as ideal combinatorial agents. Therefore, S64315 is being assessed in combination with azacitidine, a chemotherapeutic drug, and VOB560, an investigational BCL-2 inhibitor, in patients with hematopoietic cancers. Report Highlights: Research Methodology ML1 Inhibitor Drug In Clinical Trials: > 12 Drugs Commercially Approved MCL1 Inhibitor Drug: 1 (Synribo) ML1 Inhibitor Drug Clinical Trials Insight By Company, Indication and Phase Global MCL1 Inhibitor Drug Market Opportunity Outlook MCL1 Inhibitor Drug Clinical Innovation and Development Trends By Different Cancers Key Topics Covered: 1. Research Methodology 2. Introduction To MCL1 Inhibitors 2.1 MCL1 as Therapeutic Target 2.2 Role of MCL1 in Cancer 3. MCL1 Inhibitors - Mechanism of Action 3.1 Indirect Inhibition of MCL1 3.2 Direct Inhibition of MCL1 4. MCL1 Inhibitor Drug Clinical Innovation by Indication 4.1 Leukemia 4.2 Lymphoma 4.3 Multiple Myeloma 4.4 Solid Cancers 4.4.1 Breast cancer 4.4.2 Lung Cancer 4.4.3 Melanoma 4.4.4 Colorectal cancer 5. Global MCL1 Inhibitor Drug Market Opportunity Outlook 5.1 Current Clinical Research Landscape 5.2 MCL1 Inhibitor Drug Future Commercialization Opportunities 6. Global MCL1 Inhibitor Drugs Clinical Trials Overview 6.1 By Company 6.2 By Country 6.3 By Indication 6.4 By Patient Segment 6.5 By Phase 7. Global MCL1 Inhibitor Drugs Clinical Trials Insight By Company, Indication & Phase 7.1 Preclinical 7.2 Phase-I 7.3 Phase-I/II 7.4 Phase-II 8. Marketed MCL1 Inhibitor Drug Clinical Insight 9. Competitive Landscape 9.1 Amgen 9.2 Ascentage Pharma 9.3 Broad Institute 9.4 Captor Therapeutics 9.5 Cyclacel Pharmaceuticals 9.6 Gilead Sciences 9.7 Prelude Therapeutics 9.8 Servier 9.9 Sirnaomics 9.10 Teva Pharmaceutical Industries 9.11 University Of Innsbruck 9.12 Vernalis 9.13 Vichem Chemie For more information about this report visit https://www.researchandmarkets.com/r/amza4p About ResearchAndMarkets.com ResearchAndMarkets.com is the world's leading source for international market research reports and market data. We provide you with the latest data on international and regional markets, key industries, the top companies, new products and the latest trends.

成都先导技术团队编辑 FBDD（Fragment-based drug design）是一种将随机筛选和基于结构药物设计有机结合的药物发现新方法。自1981年提出以来，随着片段设计，筛选和优化技术的不断提高，FBDD逐渐从理论走向实际，成为当今主流的药物发现技术之一。迄今，全球共有4款由FBDD技术衍生的药物获得FDA批准，超过40种化合物处于临床阶段中。 FBDD相较于传统的高通量筛选（HTS）有着独特的优势，因此受到工业界和学术界的广泛关注。美国化学会自2015年以来，每年都会对公开发表的成功的fragment-to-lead案例进行总结和评估，以跟踪和讨论FBDD技术的新兴趋势和未来发展方向。近日，Wolfgang Jahnke等人在Journal of Medicinal Chemistry上发表了该系列中题为《Fragment-to-Lead Medicinal Chemistry Publications in 2019》的第五期文章（以下简称“文章”），盘点了2019年公开发表的FBDD药物开发情况。 图1：Journal of Medicinal Chemistry期刊盘点2019年公开发表的FBDD药物开发情况 文章首先对2019年的案例进行收集和研究，再根据筛选规则进行甄别，最终严格挑选出符合入选标准的20个案例，并以此为基础进行了以下几个方面的探讨。 图2：2019年符合入选标准的20个FBDD案例（图片参考：参考资料[1]） FBDD筛选靶点 与前几年形成鲜明对比的是，上述20个优化案例中只有2个激酶靶点和1个蛋白酶靶点，而有9个案例说明FBDD成功靶向了其他酶领域。此外，FBDD衍生的蛋白-蛋白相互作用（PPIs）的抑制剂的数量也非常引人注目-有6个成功的非布罗莫结构域蛋白-蛋白相互作用研究案例，包括K-RASG12D，Mcl-1和TNF。在这几个案例中，K-RASG12D的工作形成了在细胞体系中研究K-RAS的生物抑制活性检测的探针，Mcl-1的工作为临床化合物S64315/MIK665的发现铺平了道路，而TNF的工作强调了PPIs变构调节抑制剂开发的多样性。尽管大多数的PPIs的开发是寻找抑制剂，但也有一些示例试图通过FBDD技术来稳定蛋白之间的相互作用，如片段衍生的14-3-3复合物与雌激素受体ɑ，以及KRAS-SOS1复合物稳定化开发工作。 另外，其他FBDD成功的靶点包括GPCR (mGluR2)和Apolipoprotein E4。后者的工作将稳定蛋白-蛋白相互作用的概念扩展到稳定单一纯化后的蛋白，而监测FBDD在这样非典型药物作用模式中的应用是有趣的。2019年另一个有意思的概念是基于磷酸酶PTPN5/STEP的片段酶活化剂的发现。片段衍生分子作为激酶的变构激动剂已被报道过，而阐明这种激活机制在科学上同样非常有趣。 表3：2015-2019年FBDD筛选靶点分类（图片来源：参考资料[1]） 除上述提到的K-RASG12D外，2019年还有一篇关于另一个K-RAS突变类型即K-RASG12C的报道，该工作具有划时代的意义。该突变体中存在半胱氨酸，这提供了一个共价靶向的机会。Amgen和 Carmot Therapeutics采用Chemotype Evolution technology方法（化学型进化技术，一种FBDD方法）找到了针对细胞活化P2口袋的共价结合物。更重要的是，通过对这个结合物进行骨架跃迁产生了第一个针对K-RASG12C的临床抑制化合物（AMG510）。尽管严格来说这项工作不符合最初的筛选规则，但它确实完全符合FBDD技术原则，因此文章将此开创性工作突出展示。 图4：共价FBDD衍生的K-RASG12D抑制剂的发现 (图片来源：参考资料[1]) 共价FBDD案例在过去几年一直有良好的应用，有趣的是，2019年两个案例阐述了两种不同实现共价FBDD的方法。前述K-RASG12C的工作是首先筛选亲电碎片库，再在此基础上进行片段优化，而Kallikrein 5的案例是先筛选非共价碎片库，再在优化过程中加入硼杂环亲电弹头最终得到共价先导化合物。这两种方法使得大量共价FBDD的案例产出，包括cysteine protease cathepsin L, fructose-1,6-bisphosphatase和 E3 Ubiquitin Ligase HOIP。另外，共价FBDD也经历了技术的进步，例如虚拟筛选设计工具CovaDOTS，亲电片段库设计，以及进行对映体探针对的全功能化片段(FFF)的方法扩展。 FBDD筛选方法 片段与靶点的结合力较弱，其结合常数Kd值通常在μM到mM级别，因此需求较为灵敏的检测方法。据报道，目前已有超过9种检测方法被用于FBDD的片段筛选阶段，其中许多在2019年的案例研究中都有所体现。2019年最流行的片段筛选方法是bioassay（24%），NMR（22%，包括ligand-observed NMR和 Protein-observed NMR），X-ray crystallography（14%）和Thermal shift assay（10%）。与2017和2018年相比，bioassay所含比例有所降低，而X-ray crystallography的占比一如既往的高，这可能反映了市场对X ray crystallography基础设施的重大投资情况。值得一提的是，同样有相当比例（10%）的片段起始点来源于文献。 在片段优化方面，现在普遍认为FBDD是需要晶体结构信息促进的，但在没有晶体结构信息的时候同样有其他可替代的解决方法。2019年案例中有5起片段优化案例是在没有晶体结构信息下进行的，约占总数的四分之一，这种情况与往年结果类似。 图5：2019年应用于FBDD的筛选技术（左图）和2015-2019年应用于FBDD的筛选技术（右图）（图片来源：参考资料[1]） FBDD片段性质对先导化合物优化结果的影响 FBDD片段优化主要使用基团添加策略，包括片段连接，片段增长（融合）以及片段自组装等，因此需求片段具有一个较好的起点。目前，制药行业在进行片段库设计的时候除了满足基本的Ro3原则外，通常还会进行HAC，PSA，3D character等因素的考量，甚至建立相应的片段化合物库以满足筛选需求，提升片段优化的成功率。文章统计了20个2019年和131个2015-2019年fragment-lead分子对，主要对以下三个方面进行了探讨： 分子量和脂水分布系数。片段分子量范围为200-250 Da，优化得到的先导化合物分子量范围为350-400 Da，分子质量升高了约150 Da，与此同时，clogP升高了1个单位。图6：2019年片段-先导化合物分子对分子性质（上图）2015-2019年片段-先导化合物分子对分子性质（下图）（图片来源：参考资料[1]） 配体效率（Ligand efficiency, LE）。文章对2015-2019的fragment-lead分子对的LE进行统计，发现片段的LE和对应的先导化合物的LE之间没有明显趋势，配体在优化过程中，其LE可以升高也可能降低。这意味着通过合适的优化，低配体效率的片段仍然能够产生高配体效率的先导化合物。因此配体效率不应该是片段选择唯一的考量因素。片段和先导化合物的配体效率在不同的靶点之间存在细微差别，其中激酶类最高（0.42和0.40），非布罗莫结构域PPIs最低（0.32和0.31），而蛋白酶（0.39和0.33），布罗莫结构域PPIs（0.42和0.35）和其他酶（0.40和0.40）介于中间。图7：片段-先导化合物分子对配体效率，不同颜色代表不同靶点（图片来源：参考资料[1]）  3D特征（3D character）。分子的3D特征又称为“类天然产物性”，通常认为具有3D特征的化合物在筛选时候有潜在的好处（虽然缺乏实验依据）。从2015年到2019年积累数据显示，最终先导化合物的偏离平面性（DFP）独立于片段的DFP，且几乎总是大于片段的DFP。这表明片段在优化过程中变得更加“三维”。因此，片段库设计时候不一定需求很多3D特征的分子，筛选具有三维特性片段库的好处仍有待探索。图8：2015-2019年片段-先导化合物分子对偏离平面性（DFP），图中直线为片段和先导化合物偏离平面性一致（图片来源：参考资料[1]） 结语 FBDD的广泛应用表明该方法日趋成熟，但许多论文同时表明FBDD仍是一门不断发展的学科，如片段合成中新反应和新技术（微流体和自动化）的应用，片段筛选中技术的发展（如Cryo-EM，XFELs和SFX）和拓展的碎片库的创新（如MiniFrag，FragLites）等，这些帮助我们分析片段与蛋白质的相互作用，反馈库设计信息，并告诉我们如何更有效的优化片段。因此，考虑到技术持续发展，文章认为FBDD会发展地越来越好。 根据FBDD设计原则，成都先导基于自有的DEL技术对片段化合物库进行了应用拓展，实验显示出良好的结果。另外，成都先导近期收购了英国Vernalis (R & D)，凭借其20年的FBDD和SBDD开发应用经验，必然有助于这些片段化合物快速优化成临床候选化合物，并最终加速新药项目产出。 参考文献：[1] Wolfgang Jahnke et al., Fragment-to-Lead Medicinal Chemistry Publications in 2019. DOI:https://dx-doi-org.libproxy1.nus.edu.sg/10.1021/acs.jmedchem.0c01608[2] Harren Jhoti et al., Fragments: where are we now? DOI:https://doi-org.libproxy1.nus.edu.sg/10.1042/BST20190694 【关于药融圈】药融圈围绕我国生物医药产业链，针对生物医药大数据、技术和资本投资、药融园(产业园)等开展系列系统性工作，促进我国生物医药产业健康发展，完善产业链，共同面对全球合作和竞争。 点分享 点点赞点在看