更新于：2024-05-01

XIAP

凋亡抑制蛋白-3

更新于：2024-05-01

基本信息

别名

X-连锁细胞凋亡蛋白抑制剂、API3、baculoviral IAP repeat-containing 4

+ [19]

简介

Multi-functional protein which regulates not only caspases and apoptosis, but also modulates inflammatory signaling and immunity, copper homeostasis, mitogenic kinase signaling, cell proliferation, as well as cell invasion and metastasis (PubMed:11447297, PubMed:12121969, PubMed:9230442, PubMed:11257230, PubMed:11257231, PubMed:12620238, PubMed:17967870, PubMed:19473982, PubMed:20154138, PubMed:22103349, PubMed:17560374). Acts as a direct caspase inhibitor (PubMed:11257230, PubMed:11257231, PubMed:12620238). Directly bind to the active site pocket of CASP3 and CASP7 and obstructs substrate entry (PubMed:11257230, PubMed:11257231, PubMed:16352606, PubMed:16916640). Inactivates CASP9 by keeping it in a monomeric, inactive state (PubMed:12620238). Acts as an E3 ubiquitin-protein ligase regulating NF-kappa-B signaling and the target proteins for its E3 ubiquitin-protein ligase activity include: RIPK1, RIPK2, MAP3K2/MEKK2, DIABLO/SMAC, AIFM1, CCS, PTEN and BIRC5/survivin (PubMed:17967870, PubMed:19473982, PubMed:20154138, PubMed:22103349, PubMed:22607974, PubMed:30026309, PubMed:29452636, PubMed:17560374). Acts as an important regulator of innate immunity by mediating 'Lys-63'-linked polyubiquitination of RIPK2 downstream of NOD1 and NOD2, thereby transforming RIPK2 into a scaffolding protein for downstream effectors, ultimately leading to activation of the NF-kappa-B and MAP kinases signaling (PubMed:19667203, PubMed:22607974, PubMed:30026309, PubMed:29452636). 'Lys-63'-linked polyubiquitination of RIPK2 also promotes recruitment of the LUBAC complex to RIPK2 (PubMed:22607974, PubMed:29452636). Regulates the BMP signaling pathway and the SMAD and MAP3K7/TAK1 dependent pathways leading to NF-kappa-B and JNK activation (PubMed:17560374). Ubiquitination of CCS leads to enhancement of its chaperone activity toward its physiologic target, SOD1, rather than proteasomal degradation (PubMed:20154138). Ubiquitination of MAP3K2/MEKK2 and AIFM1 does not lead to proteasomal degradation (PubMed:17967870, PubMed:22103349). Plays a role in copper homeostasis by ubiquitinating COMMD1 and promoting its proteasomal degradation (PubMed:14685266). Can also function as E3 ubiquitin-protein ligase of the NEDD8 conjugation pathway, targeting effector caspases for neddylation and inactivation (PubMed:21145488). Ubiquitinates and therefore mediates the proteasomal degradation of BCL2 in response to apoptosis (PubMed:29020630). Protects cells from spontaneous formation of the ripoptosome, a large multi-protein complex that has the capability to kill cancer cells in a caspase-dependent and caspase-independent manner (PubMed:22095281). Suppresses ripoptosome formation by ubiquitinating RIPK1 and CASP8 (PubMed:22095281). Acts as a positive regulator of Wnt signaling and ubiquitinates TLE1, TLE2, TLE3, TLE4 and AES (PubMed:22304967). Ubiquitination of TLE3 results in inhibition of its interaction with TCF7L2/TCF4 thereby allowing efficient recruitment and binding of the transcriptional coactivator beta-catenin to TCF7L2/TCF4 that is required to initiate a Wnt-specific transcriptional program (PubMed:22304967).

关联

项与 XIAP 相关的药物

Xevinapant

靶点

XIAP x cIAP1 x cIAP1/cIAP2

作用机制

Inhibitors of apoptosis (IAP) protein family inhibitors [+4]

在研机构

原研机构

在研适应症

非在研适应症

最高研发阶段临床3期

首次获批国家/地区-

首次获批日期1800-01-20

Tolinapant

靶点

XIAP x cIAP1

作用机制

XIAP抑制剂 [+1]

在研机构

Astex Pharmaceuticals, Inc. [+4]

原研机构

Astex Pharmaceuticals, Inc.

在研适应症

晚期恶性实体瘤 [+11]

非在研适应症

复发性急性髓细胞白血病

最高研发阶段临床2期

首次获批国家/地区-

首次获批日期1800-01-20

APG-1387

靶点

XIAP x cIAP1/cIAP2

作用机制

XIAP抑制剂 [+1]

在研机构

原研机构

在研适应症

非在研适应症

最高研发阶段临床2期

首次获批国家/地区-

首次获批日期1800-01-20

项与 XIAP 相关的临床试验

ISRCTN11197711 / Recruiting临床1期

ASTFOX : A Phase I study of IAP antagonist, ASTX660 (tolinapant), in combination with standard of care FOLFOX chemotherapy in metastatic colorectal cancer

开始日期2024-04-30

申办/合作机构

NHS Greater Glasgow & Clyde

[+1]

NCT06084845 / Not yet recruiting临床2期

Phase II Trial of Xevinapant and Chemoradiotherapy in Adjuvant Treatment for Patients With Head and Neck Squamous Cell Carcinoma With High Risk Pathologic Features

This phase II trial compares the effect of usual radiation therapy with cisplatin/carboplatin (chemoradiation) to the addition of xevinapant with chemoradiation in patients with head and neck cancer. Radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill cancer cells and shrink tumors. Cisplatin is in a class of medications known as platinum-containing compounds. It works by killing, stopping or slowing the growth of cancer cells. Carboplatin is in a class of medications known as platinum-containing compounds. It works in a way similar to the anticancer drug cisplatin, but may be better tolerated than cisplatin. Carboplatin works by killing, stopping or slowing the growth of cancer cells. Xevinapant is a first-in-class antagonist of inhibitor of apoptosis (programmed cell death) proteins (IAPs), which leads to tumor cell death and enhances tumor cell sensitivity to chemotherapy and radiotherapy. Giving xevinapant with chemoradiation may be more effective in preventing head and neck cancer from growing or spreading than chemoradiation alone.

开始日期2024-04-12

申办/合作机构

ECOG-ACRIN Medical Research Foundation, Inc.

[+1]

NCT06056310 / Recruiting临床1期

A Single Arm, Open Label, Phase 1b Study of Xevinapant in Combination With Weekly Cisplatin and Intensity-modulated Radiotherapy to Assess Safety and Tolerability in Participants With LA SCCHN, Suitable for Definitive Chemoradiotherapy (HyperlynX)

The purpose of this study is to evaluate the tolerability and safety of Xevinapant when added to weekly cisplatin-based concurrent chemoradiotherapy (CRT) in the treatment of participants with unresectable locally advanced squamous cell carcinoma of the head and neck, suitable for definitive chemoradiotherapy.

开始日期2024-01-18

申办/合作机构

EMD Serono Research & Development Institute, Inc.

[+1]

100 项与 XIAP 相关的临床结果

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100 项与 XIAP 相关的转化医学

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0 项与 XIAP 相关的专利（医药）

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4,528

项与 XIAP 相关的文献（医药）

2024-02-21·mBio

Genetic manipulation of an Ixodes scapularis cell line.

Article

作者: Nisha Singh ; Agustin Rolandelli ; Anya J O'Neal ; L Rainer Butler ; Sourabh Samaddar ; Hanna J Laukaitis-Yousey ; Matthew Butnaru ; Stephanie E Mohr ; Norbert Perrimon ; Joao H F Pedra

Although genetic manipulation is one of the hallmarks of model organisms, its applicability to non-model species has remained difficult due to our limited understanding of their fundamental biology. For instance, manipulation of a cell line originated from the black-legged tick Ixodes scapularis, an arthropod that serves as a vector for several human pathogens, has yet to be established. Here, we demonstrate the successful genetic modification of the commonly used tick ISE6 line through ectopic expression and clustered regularly interspaced palindromic repeats [(CRISPR)/CRISPR-associated protein 9 (Cas9)] genome editing. We performed ectopic expression using nucleofection and attained CRISPR-Cas9 editing via homology-dependent recombination. Targeting the E3 ubiquitin ligase x-linked inhibitor of apoptosis (xiap) and its substrate p47 led to an alteration in molecular signaling within the immune deficiency network and increased infection of the rickettsial agent Anaplasma phagocytophilum in I. scapularis ISE6 cells. Collectively, our findings complement techniques for the genetic engineering of I. scapularis ticks, which currently limit efficient and scalable molecular genetic screens in vivo.IMPORTANCEGenetic engineering in arachnids has lagged compared to insects, largely because of substantial differences in their biology. This study unveils the implementation of ectopic expression and CRISPR-Cas9 gene editing in a tick cell line. We introduced fluorescently tagged proteins in ISE6 cells and edited its genome via homology-dependent recombination. We ablated the expression of xiap and p47, two signaling molecules present in the immune deficiency (IMD) pathway of Ixodes scapularis. Impairment of the tick IMD pathway, an analogous network of the tumor necrosis factor receptor in mammals, led to enhanced infection of the rickettsial agent Anaplasma phagocytophilum. Altogether, our findings provide a critical technical resource to the scientific community to enable a deeper understanding of biological circuits in the black-legged tick I. scapularis.

2024-02-17·Methods (San Diego, Calif.)

Design, in silico evaluation, and in vitro verification of new bivalent Smac mimetics with pro-apoptotic activity.

Article

作者: Qingsheng Huang ; Yin Peng ; Yuefeng Peng ; Huijuan Lin ; Shiqi Deng ; Shengzhong Feng ; Yanjie Wei

Bivalent Smac mimetics have been shown to possess binding affinity and pro-apoptotic activity similar to or more potent than that of native Smac, a protein dimer able to neutralize the anti-apoptotic activity of an inhibitor of caspase enzymes, XIAP, which endows cancer cells with resistance to anticancer drugs. We design five new bivalent Smac mimetics, which are formed by various linkers tethering two diazabicyclic cores being the IAP binding motifs. We built in silico models of the five mimetics by the TwistDock workflow and evaluated their conformational tendency, which suggests that compound 3, whose linker is n-hexylene, possess the highest binding potency among the five. After synthesis of these compounds, their ability in tumour cell growth inhibition and apoptosis induction displayed in experiments with SK-OV-3 and MDA-MB-231 cancer cell lines confirms our prediction. Among the five mimetics, compound 3 displays promising pro-apoptotic activity and deserves further optimization.

2024-02-13·EMBO reports

XIAP-mediated degradation of IFT88 disrupts HSC cilia to stimulate HSC activation and liver fibrosis.

Article

作者: Renjie Hong ; Yanjie Tan ; Xiaoyu Tian ; Zhenzhou Huang ; Jiaying Wang ; Hua Ni ; Jia Yang ; Weiwen Bu ; Song Yang ; Te Li ; Fan Yu ; Weilong Zhong ; Tao Sun ; Xiaohong Wang ; Dengwen Li ; Min Liu ; Yunfan Yang ; Jun Zhou

Activation of hepatic stellate cells (HSCs) plays a critical role in liver fibrosis. However, the molecular basis for HSC activation remains poorly understood. Herein, we demonstrate that primary cilia are present on quiescent HSCs but exhibit a significant loss upon HSC activation which correlates with decreased levels of the ciliary protein intraflagellar transport 88 (IFT88). Ift88-knockout mice are more susceptible to chronic carbon tetrachloride-induced liver fibrosis. Mechanistic studies show that the X-linked inhibitor of apoptosis (XIAP) functions as an E3 ubiquitin ligase for IFT88. Transforming growth factor-β (TGF-β), a profibrotic factor, enhances XIAP-mediated ubiquitination of IFT88, promoting its proteasomal degradation. Blocking XIAP-mediated IFT88 degradation ablates TGF-β-induced HSC activation and liver fibrosis. These findings reveal a previously unrecognized role for ciliary homeostasis in regulating HSC activation and identify the XIAP-IFT88 axis as a potential therapeutic target for liver fibrosis.

项与 XIAP 相关的新闻（医药）

2023-11-29

·E药经理人

亚盛医药“新故事”：耐立克再获新适应证，“王炸”单品更新临床引轰动

出海不止有一条道，但本质上殊途同归，要么唯一、要么第一、要么最佳才是“真理”。在这条路上，有价值的Biotech逐渐被投资人看到价值，并给去青睐。没有什么能比困境更益于识别一家公司的能力来得直接了。过去几年，Biotech建立多是大开大合的思路，“一下子铺上十几条管线，成立三四年内谋求上市”基本上是业内的惯常操作。然而仅仅两年的寒冬，就让这些企业备受现金流的挑战。也正因此，有价值的Biotech渐渐被投资人看到价值，并给去青睐。11月23日，恰逢耐立克（通用名：奥雷巴替尼）首个适应证获批两周年之际，亚盛医药“耐立克新适应证获批发布会暨全国首批发货仪式”在苏州正式召开。因十多年深耕细胞凋亡赛道，并做到“要么唯一，要么第一”的产品，亚盛医药逆势获得了市场青睐。根据同花顺数据，截至11月24日，亚盛医药在过去整整一年里股价上涨了46%，与此同时几乎八成的港股Biotech股价齐跌。以股价为代表的市值指标是整个市场对于一家公司的未来的综合评价。“在不确定之路上，我又多了一份坚定。”亚盛医药的一位长期投资人在耐立克第二个适应证获批当天写道。在雪球上，和他一样的长期投资者有很多。亚盛医药到底做对了什么？亚盛医药创始人杨大俊在接受E药经理人采访时的一段话从侧面给出了答案，“作为科学家，必须尊重科学，用数据说话；作为企业家，最重要的工作是要认识风险、管理风险、减少风险。我还是科学家的思维，在亚盛从Biotech转向Biopharma的过程里，我们充分尊重市场规律，在不同方向都建立了专门的团队，让专业人士去管理。当然我自己也在不断地学习。”这段话背后的潜台词，一面是亚盛在商业化转型上获得初步验证的逻辑，另一面则是亚盛对于研发和临床的态度。而这正是转型中Biotech的两个关键点。商业化，再下一城11月17日，奥雷巴替尼正式获得国家药品监督管理局（NMPA）批准，用于治疗对一代和二代酪氨酸激酶抑制剂（TKI）耐药和/或不耐受的慢性髓细胞白血病（也称慢性粒细胞白血病，简称慢粒；CML）慢性期（-CP）成年患者。这是耐立克继2021年首次获批，并成功纳入2022版国家医保药品目录后的又一重要进展。20年前，靶向BCR-ABL TKI的出现和迭代，让慢粒成为了和高血压、糖尿病一样的慢性病。但耐药的挑战长期存在，目前，仍有20%-40%的患者会在TKI治疗过程中因耐药或不耐受而治疗失败。而耐立克对BCR-ABL以及包括T315I突变在内的多种BCR-ABL突变体均有突出效果，极大地弥补了空白。随着新适应证获批，耐立克将迎来更广阔的市场空间。“这次获批最大的亮点是，适应证是任何一个二代TKI耐药后就可以使用奥雷巴替尼，相当于‘准二代’药物，而不是之前理解的‘纯三代’药物——需要3个二代TKI都耐药后才能使用。所以新适应证病人基数可能会远超过预计的三倍。”有投资人表示。公开数据显示，中国存量的慢粒患者约为20万，每年的新发患者大约在2万-3万之间。另外，整个亚洲包括中国在内，慢粒发病年龄低是显著特点，平均年龄约40岁（比国外平均要年轻20岁）。面对更大的市场，亚盛医药有没有足够的能力承接？答案是肯定的。过去三年，亚盛医药围绕耐立克建立了经过市场验证的商业化能力。从结果来看，耐立克上市第一年在只针对有特殊突变的患者的附条件批准下，获得了近2亿元的超预期销售；今年上半年耐立克持续放量，实现销售收入1.08亿元，较去年同期增长37%。尤其第二季度销售额同比增长153%。亚盛做对了什么？杨大俊分析了三点原因：内部准备、外部合作、借势政策，缺一不可。首先要提前做好准备，建立完整的销售团队。据了解，在耐立克2020年递交伴有T315I突变的慢粒适应证时，亚盛就开始着手组建商业化团队了，从市场、销售、医院准入等建立了血液瘤的专业团队。因为“亚盛的目标一直是从Biotech走向Biopharma，即要从研发到生产、再到销售的完整链条”。二是在商业化初期展开和信达的全方位合作。亚盛只有一个目标：要在最短的时间迅速扩大市场。当时这笔合作被业内解读为“现象级合作”——这是国内Biotech第一次与强销售能力的国内Biopharma合作。在第一个商业化完整年，耐立克在未进医保情况下销售达到了2亿元，无论是给杨大俊，还是给投资人都带来了“超预期”。三是以合适的价格第一时间进入医保。无论是从患者获益，还是从新药价值释放的角度，创新药以合适的价格进入医保都是最优选择。杨大俊认为，尤其对于慢病患者来说，价格对于支付的可持续性举足轻重，而“慢粒作为肿瘤中的慢病，必须力争进医保，哪怕让点利”。意外的惊喜是，“医保支持原创新药，耐立克以较小的降幅，就谈成了”。耐立克进入医保后，“患者原来需要几万元，现在报销下来可能几千元，甚至更低”。“疗效好、可负担、稀缺性”都推动了耐立克不俗的市场表现，今年第二季度销售盒数同比增长560%。如今，耐立克也成了医保局津津乐道创新药谈判的“三赢”案例。综合来看无论是从策略上，还是从执行上，亚盛的商业化能力都得到了初步的验证。更值得关注的是，相对于实体瘤产品的爆发力，血液瘤产品的累积效应将更加显著。耐立克目前正处于累积用药患者基础的前期，叠加医保后，将大大提速这一过程，为新适应证的商业化提供有力的患者基础。对于新适应证的商业化，杨大俊透露，“明年进入医保仍然是首要目标，而且对于新增适应证的降价也是可预期的，应该不会降太多。”此外在医保方面，他希望能更开放些，加速医院最后一公里的打通，以及取消审批限制，审批产品后进目录先报销等等。总归是，“要让最好的药尽快让患者用上，让好药用在刀刃上。”国际化临床，攻上高地两年多时间里，Biotech的估值方式几乎回归到了以产品临床价值为核心标准的判断，投资变得理性且克制。而这一年支撑亚盛估值上升的，既离不开商业化上的超预期表现，更离不开他在临床上连续达成的里程碑，二者互为助益。今年8月，亚盛医药的APG-2575获FDA批准开展一项全球关键注册性3期临床研究，针对经治CLL/SLL患者，该研究结果将支持全球上市。消息一经发布便引发该公司股价在三个交易日内大涨超16%。而在一个月前，该研究在clinicaltrails.gov挂网显示启动，再次引发了小范围内的轰动和讨论。作为亚盛医药最“王炸”的产品，APG-2575被投资人看成其首个10亿美元分子，关键里程碑进展自然备受关注。不过更确切地说，业内的焦点在于该试验独特的临床设计方案。据业内人士分析，APG-2575的独特优势在于快速爬坡。相比较维奈克拉（全球唯一上市的BCL-2抑制剂）需每周递增给药，超过一个月才能达到治疗剂量，亚盛医药的APG-2575能够实现每日递增，快速达到目标治疗剂量。“该独特优势或将成为APG-2575上市后抢占市场的杀招”。据业内人士分析，APG-2575的独特优势在于快速爬坡。相比较维奈克拉（全球唯一上市的BCL-2抑制剂）需每周递增给药，超过一个月才能达到治疗剂量，亚盛医药的APG-2575能够实现每日递增，快速达到目标治疗剂量。“该独特优势将成为APG-2575上市后抢占市场的杀招。当然，采用长期剂量递增的临床设计背后是安全性问题，这是治疗CLL/SLL的常见问题，比如BTK里的伊布替尼，以及BCL-2里的维奈克拉在安全性上均有可以提升的空间，这也给了后来者空间。APG-2575除了在剂量递增上更便捷外，其在安全性上明显高于维奈克拉，特别在肿痛溶解综合征(TLS) 远远低于；在有效性上，该联合疗法疗效显著超越了单独用BTK或者BCL-2抑制剂。2022 ASH年会的口头报告显示，APG-2575联合阿卡替尼在R/R CLL/SLL患者中的客观反应率(ORR)达98%、在初治CLL/SLL患者中的ORR达100%，且仍然保持了与单药治疗相当的良好安全性。临床设计是巧妙的，但也有风险，而且国际性三期临床花费不会低。“小Biotech输不起国际大三期”反映了诸多投资者的担忧。对此，亚盛早就未雨绸缪。2020年6月，亚盛与阿斯利康血液研发卓越中心Acerta制药达成临床研究合作，共同探索“APG-2575+阿卡替尼”在复发或难治 CLL/SLL的全球多中心研究。加上前面的临床设计，将大大降低国际性三期临床的成本。而今合作进一步扩围，投资者的疑虑进一步消解。就在一个月前，亚盛再次与阿斯利康达成临床合作协议，双方将共同进行“APG-2575+阿卡替尼”的注册性III期临床研究，用于初治CLL/SLL患者的一线治疗。不久前该试验刚获CDE临床许可，是亚盛医药今年的又一临床里程碑。值得关注的是，这两大关键里程碑将推动亚盛医药在2025年并入全球创新药企的轨道。底牌：专注和创新“条条大路通罗马”，亚盛展示了Biotech并轨全球的一种路径。但并非所有Biotech都能走这条路，近日在FDA接连获批的国产新药阐述了“要么第一，要么唯一，要么最佳”的国际化“真理”。这正是亚盛二十余年来一直在坚持的。20年前，除了雅培所有MNC药企都不看好细胞凋亡通路抑制剂，亚盛坚定地选择从这个方向出发，并深耕小分子领域，成为了该方向的全球领先。“我们成立时就想做全球的创新，要引领世界潮流，而不是跟随式的。”基于长期的专注，以及对自主研发的坚定投入，亚盛形成了少而精的差异化临床管线。其研发管线布局了9个产品，并围绕于此布局了40多个临床试验。除了奥雷巴替尼、BCL-2抑制剂，还有MDM2-p53的抑制剂、IAP/XIAP抑制剂、Bcl-2/Bcl-xL抑制剂、FAK/ALK/ROS1抑制剂等等。这些产品的共同特点是：一是真正的原创。二是瞄准全球市场。在杨大俊看来，要真正做到全球上市，三个维度非常重要：第一，核心产品必须有结构性的专利保护，这也是亚盛最重要的护城河。据了解，目前亚盛现在授权的专利约500个，超过半数是海外授权。第二，要按照国际标准来做临床试验，在中国和美国都要按照严格的国际标准来做，从中国走向世界；第三，必须强调临床价值，强调便宜在美国并不会对上市有利。正如亚盛在细胞凋亡领域的“王者”地位，杨大俊本人也因在基因遗传学上的长期深耕，近日获得“谈家桢生命科学奖”。据了解，该奖项是由谈家桢提议，经国家科技部批准设立的生命科学技术奖项。谈家桢是中国遗传学的鼻祖，要获得该奖项相当不易。杨大俊表示，获得该奖项一方面由于自己40年前从事的都是遗传学方向，另一方面是对耐立克的认可，BCR-ABL抑制剂的发现过程是遗传学上的重要里程碑。对于亚盛的未来，杨大俊表示，在国内，亚盛要成为全方位的Biopharma，集研发、生产、商业化为一体；在国际，亚盛的目标则是尽快推进通过FDA批准的临床试验在全球进行开发，做到在全球批准上市。同时亚盛作为一家上市企业，所以“我们也希望在2026年做到通过产品的销售利润反哺自主研发，真正从Biotech成长为Biopharma”。延伸阅读：13年磨一剑，三代“格列卫”上市后，细胞凋亡王者亚盛医药的下一站在哪？商业化首战告捷、专利构建全球壁垒，这家药企凭什么活成了最理想的Biotech模样？登记邮箱信息订阅E药经理人信息服务扫描二维码精彩推荐CM10 | 集采 | 国谈 | 医保动态 | 药审 | 人才 | 薪资 | 榜单 | CAR-T | PD-1 | mRNA | 单抗 | 商业化 | 国际化｜猎药人系列专题启思会 | 声音·责任 | 创百汇 | E药经理人理事会 | 微解药直播 | 大国新药 | 营销硬观点 | 投资人去哪儿 | 分析师看赛道 | 药事每周谈 | 医药界·E药经理人 | 中国医药手册创新100强榜单 | 恒瑞 | 中国生物制药 | 百济 | 石药 | 信达 | 君实 | 复宏汉霖｜翰森 | 康方生物 | 上海医药 | 和黄医药 | 东阳光药 | 荣昌 | 亚盛医药 | 齐鲁制药 | 康宁杰瑞 | 贝达药业 | 微芯生物 | 复星医药｜再鼎医药｜亚虹医药跨国药企50强榜单 | 辉瑞 | 艾伯维 | 诺华 | 强生 | 罗氏 | BMS | 默克 | 赛诺菲 | AZ | GSK | 武田 | 吉利德科学 | 礼来 | 安进 | 诺和诺德 | 拜耳 | 莫德纳 | BI | 晖致 | 再生元

核酸药物

2023-11-17

·BioSpace

Taiho Oncology and Astex Pharmaceuticals Announce Data Presentations at the 65th ASH Annual Meeting

[17-November-2023] Real-world evidence on use of oral decitabine and cedazuridine in the treatment of myelodysplastic syndromes to be featured in an oral presentation; results of several additional studies in hematological malignancies were accepted for poster presentations PRINCETON, N.J. and PLEASANTON, Calif., Nov. 17, 2023 /PRNewswire/ -- Taiho Oncology Inc. and Astex Pharmaceuticals, Inc. announced today details of studies to be presented at the 65th American Society of Hematology (ASH) Annual Meeting, to be held Dec. 9-12, 2023, in San Diego. Among these data are the results of a real-world study of oral decitabine and cedazuridine in patients with myelodysplastic syndromes (MDS), which will be featured in an oral presentation. "Real-world data in healthcare is invaluable as it provides us with a closer look at actual patient experiences outside the clinical trial setting," said Tehseen Salimi, MD, MHA, Senior Vice President Medical Affairs, Taiho Oncology. "This study is the first to explore how an oral therapy may help patients with MDS adhere to their treatment regimen, while reducing both personal and disease burden. Oral decitabine and cedazuridine is a potentially important treatment option for people living with this form of cancer." Below are viewing details of this oral presentation. The above study was sponsored by Taiho Oncology. In addition, investigational compounds from Astex Pharmaceuticals that are currently in various stages of clinical development will be featured in several poster presentations. The above studies are being sponsored by Astex Pharmaceuticals, Inc. About Taiho Oncology, Inc. The mission of Taiho Oncology, Inc. is to improve the lives of patients with cancer, their families and their caregivers. The company specializes in the development and commercialization of orally administered anti-cancer agents for various tumor types. Taiho Oncology has a robust pipeline of small molecule clinical candidates targeting solid tumor and hematological malignancies, with additional candidates in pre-clinical development. Taiho Oncology is a subsidiary of Taiho Pharmaceutical Co., Ltd. which is part of Otsuka Holdings Co., Ltd. Taiho Oncology is headquartered in Princeton, New Jersey and oversees its parent company's European and Canadian operations, which are located in Zug, Switzerland and Oakville, Ontario, Canada. For more information, visit , and follow us on LinkedIn and Twitter. About Astex Pharmaceuticals, Inc. Astex Pharmaceuticals, Inc. is committed to the fight against cancer. Astex is developing a proprietary pipeline of novel therapies for the treatment of solid tumors and hematological malignancies. Astex is a member of the Otsuka group of companies. The group also includes Otsuka Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., and Taiho Oncology, Inc. Astex, the Astex logo, Taiho Oncology, and the Taiho Oncology logo are registered trademarks of Otsuka Holdings Co., Ltd. or its subsidiaries. Taiho Oncology Contact: Judy Kay Moore (574) 526-2369 jumoore@taihooncology.com Astex Pharmaceuticals: Martin Buckland Astex Pharmaceuticals, Inc. (+1) 925-560-0100 martin.buckland@astx.com INQ-PM-US-0512 1 Investigational Oral DNA Methyltransferase Inhibitor 2 X-Linked Inhibitor of Apoptosis Protein (XIAP)/Cellular Inhibitor of Apoptosis Protein (cIAP) Antagonist - Astex Pharmaceuticals, Inc. investigational agent being developed in collaboration with Taiho Oncology, Inc.

ASH会议

2023-09-21

·药研网

新模式的兴起 —— 降解抗体偶联药物（DAC）

随着ADC药物的兴起，多种偶联模式也随之出现。近期，Seagen与Nurix达成降解抗体偶联药物（DAC）的开发合作，预付款6000万美元，里程碑付款共达34亿美元。DAC相较于ADC来说，还处于新兴的，未经充分验证的初步开发阶段，本文将详细介绍DAC的概念、应用及最新进展。目前PROTAC药物由三部分构成，包括目标蛋白结合物、泛素连接酶配体和连接子。但PROTAC通常面临细胞摄取差和生物利用度低的问题，在健康细胞和癌细胞之间缺乏区分可能会引发脱靶毒性，而DAC模式的出现为PROTAC药物提供了新的思路。DAC结构设计DAC和ADC结构比较相似，包括单抗、linker和有效载荷三部分。最大区别在于有效载荷方面，ADC 通常用于输送小分子毒素，而 DAC 则用于输送 PROTAC 和分子胶。ADC 和 DAC 遵循相同的原则：选择性地转运payload，同时尽量减少脱靶效应。ADC中的有效载荷具有更强的细胞杀伤活性，因此，DAR通常为4-8或2-6，具体取决于偶联方法。相比之下，DAC所需的DAR要高于ADC，因为TPD分子的药效通常弱于 ADC毒素。根据有效载荷的数量和连接子化学性质，会产生聚集、低效和药代动力学问题。最后，在制备TPD时，应考虑使用额外的官能团与连接子连接抗体。DAC机制DAC与ADC机制相似，DAC在血液循环中尽可能保持稳定，随后抗体特异性识别肿瘤相关抗原，DAC被内化至溶酶体，在蛋白水解和酸性环境中，DAC被降解，释放有效载荷（PROTAC），随后发挥作用。研究进展BRD4-Targeting DAC首次被研究报道的DAC是BRD4 DAC，由CLL1单抗和BRD4 PROTAC（GNE-987）构成，相关文章是由基因泰克和药明康德联合发表。在研究中，GNE-987相较于MZ1和ARV-771具有更好的降解作用和AML癌细胞毒性，但由于体外和体内 DMPK 特性不佳，因此需要一种合适的递送方案。由于CLL1在AML细胞表面高表达，之前对抗体半胱氨酸扫描的研究也发现，半胱氨酸残基的位置（LC-K149、HC-L174、HC-Y373）经过设计后，可表现出良好的体内稳定性。作者采用了“direct-disulfide”偶联策略，使用含有活化二硫化物的甲硫磺酰（MTS）基团与 CLL1 抗体上的六个半胱氨酸残基（DAR ≈ 6.0）偶联，没有出现明显的聚集问题。再利用降解剂原有的羟脯氨酸功能来连接linker，构建成DAC 4。与靶向HER2的对照偶联物和降解剂GNE-987相比，DAC 4 对 HL-60 AML 和 EOL-1 AML 的疗效明显更强。表明DAC的构建可以克服degrader药代动力学的不良特性。DAC 4的药代动力学显示，其在体内的稳定性较高。后续他们又开发了靶向STEAP1和靶向CLL1的BRD4 DAC，DAR为2，即DAC 5a和DAC 5b，但BRD4降解效果不佳。但通过提高DAR的方式构建的DAC 5c（DAR=6）显示，其具有更好的BRD4降解效果。接下来，作者考虑将降解剂中的胺或苯胺作为偶联位点。加入苯胺分子，同时使用强效降解剂，构建的DAC 9a单次静脉注射在PC3-S1小鼠模型中显示出剂量依赖性的肿瘤生长抑制作用2020年，Maneiro等人报道了将ARV-711与HER2抗体（曲妥珠单抗）偶联的DAC 12，DAR为4。DAC 12 在PBS中很稳定，培养4小时后，其完好率为 98.8%，24 小时后可达 83.5%。DAC 12在 HER2+ 细胞中显示出对 BRD4 的选择性降解。Erα-Targeting DACDragovich 等人还展示了两种不同的 Erα 靶向降解剂13和15（图a,b）。13由连接酶配体 XIAP 和选择性雌激素受体调节剂他莫昔芬偶联，表现出对 Erα 的强效降解作用。在首次尝试中，他们利用他莫昔芬的游离羟基，通过缬氨酸-瓜氨酸-对氨基苄氧基连接子与 HER2 Ab偶联（14），成功证明了靶蛋白的降解。之后构建了PROTAC 15 与 VHL 配体合成的 DAC。并利用 VHL 的羟基、通过碳酸基二硫连接子和焦磷酸二酯连接子合成了相应的DAC 16和 17。但这些偶联物仅表现出中等稳定性。TGFβR2, BRM-Targeting DACCRBN（cereblon）连接的降解剂 18 使用赖氨酸作为连接体连接到 HER2 上的不可裂解酰胺连接体上，构建了TGFβR2 DAC（19），在 24 小时和 48 小时后显示出了所需的 TGFβR2 靶向降解水平。还有BRM降解剂（20），起初该降解剂是由 Arvinas 公司和基因泰克公司于 2019 年开发的。基因泰克公司进一步展示了基于降解剂20的DAC平台，该DAC使用二硫键连接子偶联与CD22细胞表面受体结合的单抗（21）。其异种移植数据显示，靶向 BRM 蛋白水平的降解具有高效性和抗原依赖性。GSPT1-Targeting DAC2022 年，Orum公司针对 GSPT1 蛋白开发的DAC（ORM-5029）进入了首个 I 期临床试验，其由高活性 GSPT1 降解剂 SMol006 通过 Val-Cit PABc 连接子与 pertuzumab 偶联，临床前数据中，与SMol006、Kadcyla和/或Enhertu治疗相比，ORM-5029治疗HER2表达细胞系的疗效增强了10-1000倍。参考：https://doi-org.libproxy1.nus.edu.sg/10.1021/acs.jmedchem.2c01791细胞系产品查询投稿丨商务合作加入交流群往期推荐恒瑞医药生物药管线全梳理中生制药企业梳理石药集团生物药技术平台及管线梳理降糖减重外，GLP-1的其他作用汇总点击下方“药研网”，关注更多精彩内容

抗体药物偶联物蛋白降解靶向嵌合体