VOB-560

2024年5月4日，百济神州公司在Journal of Medicinal Chemistry杂志上发表了以“Discovery of the Clinical Candidate Sonrotoclax (BGB-11417), a Highly Potent and Selective Inhibitor for Both WT and G101V Mutant Bcl-2”为题的文章，该文章介绍了细胞淋巴瘤-2（Bcl-2）选择性抑制剂Sonrotoclax (BGB-11417)的发现，对WT Bcl-2和G101V突变体都有很强的体内外抑制活性。该抑制剂目前处于临床II/III期评估阶段，作为单一疗法和联合疗法使用。细胞凋亡是细胞程序性死亡的一种形式，逃避细胞凋亡对肿瘤的发展和维持至关重要。B细胞淋巴瘤-2（Bcl-2）作为一种抗凋亡蛋白，通过抑制促凋亡蛋白来促进细胞存活。Bcl-2在淋巴恶性肿瘤和一些实体瘤的存活过程中起着主导作用，并经常在这些癌症中高表达，它通过与促凋亡蛋白的BH3结构域结合来封闭促凋亡蛋白，从而发挥其功能。因此，抑制细胞内这些蛋白-蛋白之间的相互作用是针对Bcl-2失调导致的癌细胞异常存活的一种有吸引力的策略。过去二十年，已经报道了很多Bcl-2抑制剂（图1），如S65487（2, I期）、lisaftoclax（APG-2575, 3）、lacutoclax（LP-108, 4）、AZD4320（5, II期）和APG-1252（6, II期）。百济神州公司在Bcl-2/Bcl-xL双重抑制剂ABT-737 (1a)及其口服生物可利用类似物ABT-263 (navitoclax, 1b)的基础上开发出了首个选择性Bcl-2（Bcl-xL-sparing）抑制剂ABT-199（venetoclax, 1c），用于治疗Bcl-2依赖性恶性肿瘤。但ABT-199（venetoclax）有限的效力无法在其他Bcl-2介导的恶性肿瘤（如弥漫性大B细胞淋巴瘤）中产生强而持久的临床益处，而且据报道，多种复发性Bcl-2突变（如G101V）可介导长期治疗后对venetoclax的耐药。图1 选择性的Bcl-2抑制剂化合物结构设计为了合理地设计一种能更有效地抑制WT Bcl-2蛋白和G101V突变的Bcl-2抑制剂，作者分析了已报道的Bcl-2抑制剂的结合模式。这些化合物与Bcl-2的P2和P4口袋（ABT-263，图 2a）或仅与P2口袋（S55746，图 2b）结合，实现了良好的结合亲和力，而且P2口袋相对灵活，可兼容各种结构。此外，Bcl-2 G101V: venetoclax共晶体结构（PDB：6O0L）揭示了G101V突变体经venetoclax处理后获得抗性的分子基础。由于Venetoclax的氯苯分子深深插入P2口袋，当G101突变为体积更大的缬氨酸时，一个关键残基Glu152被推入P2口袋的底部，与氯苯产生立体冲突；这导致Venetoclax与Bcl-2 G101V的结合亲和力下降了约180倍。因此，作者进一步优化该化合物的分子结构，增强该化合物与Bcl-2 WT的结合亲和力，并恢复对突变体（尤其是 G101V）的抑制作用。图2 Bcl-2与(a) ABT-263（PDB ID：4LVT）和(b) S55746（PDB ID：6GL8）的晶体结构结构优化作者最初改变了Venetoclax中的哌啶连接物，以探索P2口袋的容积和灵活性，并以Bcl-2 WT为重点进行初步SAR研究。化合物7（图 3）中的长扭曲连接体双环四氢吡唑并[1,5-a]嘧啶在Bcl-2 WT生化实验中具有良好的药效（IC50 = 45 nM），表明P2口袋具有较大的容积和灵活性。过去除二甲基环己烯基团以大幅缩短化合物8中的连接体，进一步证明了其灵活性，但其效力仅下降了1倍（IC50 = 105 nM）。通过改变过于僵硬或过短的双环连接体，获得化合物9a，其生物活性提高了近4倍。以此为改造方向进一步进行结构优化。图3 起始化合物7, 8, 9a的结构优化首先，作者探索了9a中的对氯苯部分对Bcl-2 WT和Bcl-xL及RS4;11和MOLT-4细胞的影响，进行了一系列的结构优化。其中，具有环丙基的化合物9s是最有效的类似物（图4A）。随后作者在9s基础上进行linker的优化，设计并合成了一系列具有不同linker的化合物（图4B）。引入了一种更坚硬的螺连接体7-氮杂螺[3.5]壬烷，生成化合物10r，其生化效力显着提高到0.049 nM，细胞效力增加到5.8 nM。S对映异构体（S-10r）的效力是相应的R对映异构体（R-10r）的∼31倍（0.039 nM vs 1.2 nM）。与Bcl-2蛋白的结合模式分析表明，S-10r的环丙基和吡咯烷基团之间的中心苯环浅结合，并与Met115的侧链形成磺酰基-π相互作用（图5），这有助于提高对Bcl-xL的选择性。S-10r的环丙基诱导P2残基形成不同的构象，包括Asp111、Phe112和Met115，从而产生额外的子口袋。这些额外的疏水相互作用有助于提高S-10r的效力。与Venetoclax相比，S-10r对Bcl-2 G101V的生化效力显著提高（1.3 nM vs 25 nM）图4 不同左侧基团的结构优化（A）和linker的优化（B）图5 （a）S-9c与Venetoclax和（b）S-10r与Venetoclax的晶体结构叠加。（c）S-10r与Bcl-2结合模式随后，作者用S-10r进一步修饰P2口袋的结合基团，以进一步提高对G101V的效力。在一系列优化的化合物中，异丙基类似物11g的效力最高（图6）。为了确定环丙基（S-10r）、异丙基（11g）和N,N-二甲氨基（11n）之间的最佳邻位取代基，作者进一步比较了它们的肝微粒体（LM）稳定性和CYP抑制曲线（表1）。其中，11g在所有评估物种中具有更均衡的LM稳定性和最低的人体CLint以及最弱的CYP2C9抑制性。最后，为了降低DDIs的风险并进一步提高WT Bcl-2和G101V突变体的效力，作者基于先导化合物11g筛选了各种右侧基团优化的化合物。反式异构体12e（也称为BGB-11417）在生化测定中显示出改进的IC50，对Bcl-2 WT和G101V的效力分别为0.019和0.34 nM。当1,4-二氧六环掺入右侧时，作者发现S对映异构体（12h）对CYP2C9没有明显的抑制作用。初步SAR研究表明，化合物12e具有最佳的生化活性和细胞效力。化合物12e与G101V突变体保持强相互作用，表面等离子体共振（SPR）测定（KD = 0.24 nM），而Venetoclax的KD值为29 nM。同时，化合物12e比其他临床Bcl-2选择性抑制剂更有效（表2）。表1 肝微粒体稳定性与CYP抑制作用的比较图6 基于S-10r进行P2口袋的结合基团优化（A）和右侧基团的优化（B）表2 化合物12e比其他临床Bcl-2选择性抑制剂更有效体外研究新型Bcl-2 抑制剂12e的药物特性12e除了不抑制各种CYP酶所表明的低DDI风险外，还在所有四种常见物种中表现出良好的体外肝微粒体稳定性，其中小鼠的CLint仍然最高。随后进一步研究了动物的药代动力学（PK）。总体而言，12e在小鼠和狗体内均表现出良好的PK曲线。由于狗的固有清除率低于小鼠（12e为28.9 vs 48.7），狗的体内清除率也远低于小鼠。因此，狗的Cmax和AUC远高于小鼠，口服的生物利用度也是如此。表3 12e与12h的类药性比较体内PD和疗效研究单剂量口服12e可显著诱导肿瘤中已裂解的caspase-3的表达，由于其出色的体外药效以及在血浆和肿瘤中可接受的暴露量（图7）。在RS4;11携带NCG小鼠体内评估了化合物12e的体内疗效（图8）。化合物12e在7.5 mg/kg的较低剂量下表现出了良好的耐受性和显著的抗肿瘤活性。在治疗后21天的平均肿瘤生长抑制（TGI）值为103%，而venetoclax仅显示出中度的肿瘤生长抑制（TGI为86%）。在对venetoclax不敏感的模型中，12e的效力显著改善，并在DLBCL异种移植模型和RS4;11 Bcl-2 G101V异种移植模型中显示出显著优于venetoclax的PD和疗效。同时，12e对血液系统肿瘤，包括部分NHL有较好的疗效，并有可能克服Bcl-2 G101V突变和其他可能的突变。图7 单次口服12e、12h和venetoclax（50 mg/kg）后，在携带RS4;11异种移植肿瘤的NCG小鼠体内测定的PD/PK数据图8 口服RS4后12e、12h和venetoclax的体内异种移植物活性总结本文开发了一种高效的选择性Bcl-2抑制剂BGB-11417 (12e, sonrotoclax)，该抑制剂可与Bcl-2蛋白的P2口袋形成浅而广泛的相互作用。通过与Bcl-2的共晶体结构，初步确定了一个新的邻位上有烷基取代的苯基吡咯烷片段可以与P2口袋进行相互作用。随后对Linker进行筛选获得了刚性的螺旋连接子7-azaspiro[3.5]壬烷。然后对P2口袋结合部分及右侧基团进一步进行优化，得到化合物BGB-11417 (12e)，其对野生型Bcl-2和G101V突变体以及其他突变体的体外抑制活性均优于venetoclax，且选择性优于Bcl-xL。BGB-11417在异种移植小鼠模型中显著更高的疗效进一步证明了其对venetoclax的优越性。目前，BGB-11417已在ⅰ/ⅱ期临床试验中显示出良好的安全性，并进入ⅲ期临床试验进一步评估其单药及联合治疗CLL、NHL等血液系统恶性肿瘤患者的疗效和安全性。原文链接：https://pubs.acs.org/doi/10.1021/acs.jmedchem.4c00027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↓

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.