PUMA-ALI-1201 is a randomized, dose optimization, multicenter, Phase 2 study of alisertib administered in combination with endocrine therapy in participants with pathology-confirmed HR-positive/HER2-negative metastatic breast cancer (MBC) following progression on or after at least two prior lines of endocrine therapy in the recurrent or metastatic setting. This study is intended to evaluate the optimal alisertib dose administered in combination with the selected endocrine therapy. The study is also planned to evaluate the efficacy, safety, and pharmacokinetics of alisertib in combination with endocrine and to identify the biomarker-defined subgroup(s) that may benefit most from combined alisertib and endocrine therapy.

开始日期2024-11-19

申办/合作机构

Puma Biotechnology, Inc.

NCT06095505

/ Recruiting临床2期

A Phase 2 Study of Alisertib in Patients With Extensive Stage Small Cell Lung Cancer

PUMA-ALI-4201 is a Phase 2 study evaluating alisertib monotherapy in patients with pathologically-confirmed small cell lung cancer (SCLC) following progression on or after treatment with one platinum-based chemotherapy and anti-PD-L1 immunotherapy agent. Up to one additional systemic anti-cancer therapy for SCLC is allowed, for a total of up to two prior lines of therapy. This study is intended to identify the biomarker-defined subgroup(s) that may benefit most from alisertib treatment and to evaluate the efficacy, safety, and pharmacokinetics of alisertib.

开始日期2024-02-08

申办/合作机构

Puma Biotechnology, Inc.

NCT04555837

/ Completed临床1/2期IIT

A Phase I-II, Open Label Study Evaluating the Safety and Efficacy of Alisertib and Pembrolizumab in Patients With Rb-Deficient Head and Neck Squamous Cell Carcinomas

This phase I/II trial investigates the best dose and effect of alisertib in combination with pembrolizumab in treating patients with Rb-deficient head and neck squamous cell cancer. Alisertib may help block the growth of cancer.. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the tumor, and may interfere with the ability of tumor cells to grow and spread. Giving alisertib in combination with pembrolizumab may help control Rb-deficient head and neck squamous cell cancer. HPV positive head and neck cancers are Rb-deficient.

开始日期2020-09-15

申办/合作机构

The University of Texas MD Anderson Cancer Center

[+1]

100 项与 Alisertib 相关的临床结果

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100 项与 Alisertib 相关的转化医学

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100 项与 Alisertib 相关的专利（医药）

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651

项与 Alisertib 相关的文献（医药）

2025-04-01·CANCER SCIENCE

AURKA/PLK1/CDC25C Axis as a Novel Therapeutic Target in INI1‐Deficient Epithelioid Sarcoma

Article

作者: Nakai, Sho ; Outani, Hidetatsu ; Inoue, Akitomo ; Takami, Haruna ; Kotani, Yuki ; Mae, Hirokazu ; Okada, Seiji ; Imura, Yoshinori

ABSTRACT:

Effective therapeutic strategies for epithelioid sarcoma (EpS), a high‐grade soft tissue sarcoma characterized by loss of integrase interactor 1 (INI1), have not yet been developed. The present study therefore investigated the association between INI1 loss and upregulation of the aurora kinase A (AURKA)/polo‐like kinase 1 (PLK1)/cell division cycle 25C (CDC25C) axis, as well as the therapeutic relevance of this axis in EpS. Notably, our findings showed that the reintroduction of INI1 in VA‐ES‐BJ cells significantly reduced proliferation, mitigated tumorigenicity, and negatively regulated the expression of AURKA and its downstream effectors, as well as the activation of PLK1 and CDC25C. These results suggest that INI1 deficiency enhanced EpS growth by upregulating the AURKA/PLK1/CDC25C axis. AURKA silencing using siRNAs inhibited VA‐ES‐BJ and Asra‐EPS cell proliferation by inactivating PLK1 and CDC25C. Alisertib, a selective AURKA inhibitor, exerted markedly greater antiproliferative effects on EpS cells than on normal human dermal fibroblasts, and these effects were dependent on INI1 deficiency. Inhibition of AURKA activity by alisertib induced G2/M cell cycle arrest and apoptosis via the inactivation of AURKA downstream effectors in EpS cells. Alisertib also significantly decreased VA‐ES‐BJ xenograft tumor growth. Taken together, our findings revealed that INI1 loss in EpS cells enhances the expression of AURKA and its downstream effectors and persistently activates PLK1 and CDC25C mediated by AURKA, making the cells reliant on the AURKA/PLK1/CDC25C axis. Therefore, the AURKA/PLK1/CDC25C axis activated by INI1 deficiency could serve as a novel therapeutic target for this devastating disease.

2025-04-01·iScience

Combination therapy with alisertib enhances the anti-tumor immunity induced by a liver cancer vaccine

Article

作者: Zhang, Jing ; Xue, Fang ; Liu, Jing ; Zhu, Ningning ; Li, Xueer ; Tang, Shuting ; Duan, Huan ; Wu, Jinyan ; Zhang, Mengli ; Wang, Rui

Alisertib is a potent aurora A kinase inhibitor in clinical trials for cancer treatment, but its efficacy on cancer vaccines remains unclear. Here, we developed a DNA vaccine targeting glypican-3 (pGPC3) and evaluated its efficacy with alisertib in hepatocellular carcinoma (HCC) models. The combination therapy of pGPC3 vaccine and alisertib significantly inhibited subcutaneous tumor growth, enhanced the induction and maturation of CD11c⁺ and CD8⁺CD11c⁺ dendritic cells (DCs), and expanded tumor-specific CD8⁺ T cell responses. CD8⁺ T cell depletion abolished the anti-tumor effects, underscoring the essential role of functional CD8⁺ T cell responses. Moreover, the combined treatment promoted memory CD8⁺ T cell induction, providing long-term protection. In liver orthotopic tumor models, the combination of pGPC3 vaccine and alisertib demonstrated potent therapeutic efficacy through CD8⁺ T cell responses. These results indicate that alisertib enhances the pGPC3 vaccine's therapeutic effect, offering a promising strategy for HCC treatment.

2025-04-01·JOURNAL OF BIOLOGICAL CHEMISTRY

Alisertib impairs the stemness of hepatocellular carcinoma by inhibiting purine synthesis

Article

作者: Xu, Ye ; Xiang, Wei ; Liu, Wenfeng ; Du, Xiaojing ; Hu, Sunkuan ; Qi, Zhuoran ; Ma, Yifan ; Shen, Xizhong ; Luo, Jie

Hepatocellular carcinoma tumor-repopulating cells (HCC-TRCs) drive disease progression, yet their purine metabolism mechanisms remain poorly understood. This study revealed that the stemness index, strongly linked to poor HCC prognosis, exhibited a robust positive correlation with purine metabolism through single-sample gene set enrichment analysis (ssGSEA). Integrated drug screening across CTRP, GDSC, and PRISM databases identified alisertib, an Aurora kinase A inhibitor, as a potent agent targeting stemness. Using fibrin gel-based 3D-cultured HCC-TRCs, mechanistic studies demonstrated that alisertib suppresses xanthine and hypoxanthine production by inhibiting the AURKA/AKT signaling axis. This disruption markedly impaired tumor spheroid formation, migration, and invasion in vitro, while significantly suppressing tumor growth in vivo-effects reversible by the AKT agonist SC79. Our findings revealed a novel therapeutic strategy targeting purine metabolism through AURKA/AKT axis inhibition, effectively eliminating HCC-TRCs.

项与 Alisertib 相关的新闻（医药）

2025-04-30

·GlobeNewswire-Health Care

Er-Kim Announces Exclusive Distribution Agreement with Puma Biotechnology to Commercialize NERLYNX® (neratinib) for Breast Cancer Patients

This collaboration will provide early-stage HER2-positive breast cancer patients with access to the targeted therapy that can reduce the risk of cancer recurrence and spread ATHENS, Greece and LOS ANGELES, April 30, 2025 (GLOBE NEWSWIRE) -- Er-Kim, an international pharmaceutical company specializing in the commercialization of novel therapies in the EMEA region, today announced that it has signed an agreement with Puma Biotechnology, Inc. (NASDAQ: PBYI) to commercialize NERLYNX® (neratinib) in select countries in Eastern Europe and Central Asia. NERLYNX is designed to block human epidermal growth factor receptor 2 (HER2) in order to treat and limit breast cancer metastasis. Under the agreement, Er-Kim is appointed as the distribution partner for NERLYNX in Armenia, Azerbaijan, Belarus, Georgia, Kazakhstan, Kyrgyzstan, Russia, Tajikistan, Turkmenistan, and Uzbekistan. NERLYNX is a prescription medicine used alone to treat adults with early-stage HER2-positive breast cancer and who have previously been treated with trastuzumab-based therapy. NERLYNX is also approved for use with a medicine called capecitabine to treat adults with HER2-positive breast cancer that has spread to other parts of the body (metastatic) and who have received 2 or more anti-HER2 therapy medicines for metastatic breast cancer. According to the International Agency for Research on Cancer (IARC), globally, breast cancer is the most common cancer type among women and the second most common cancer type overall. An estimated 2.3 million new breast cancer cases and 670,000 breast cancer-related deaths occurred worldwide in 2022. However, the burden of breast cancer is not evenly distributed across different world regions. “While breast cancer affects individuals globally, treatment availability varies considerably across regions,” said Cem Zorlular, Chief Executive Officer of Er-Kim. “That is why we are pleased to be working with Puma Biotechnology to support access to NERLYNX in Russia and most of the Commonwealth of Independent States (CIS) for patients with early-stage breast cancer. Er-Kim has a long history of providing treatments in the EMEA region, particularly in women's health.” About Er-Kim Established in 1981, Er-Kim stands at the forefront of biopharmaceutical innovation, partnering with over 40 global leaders to revolutionize patient care in key international markets. Our pioneering business models, tailored for sustainability and flexibility, have positioned us as a full-service solution, extending our reach to over 600 million patients through our fully owned affiliates. With a dedicated team of over 280 professionals worldwide and revenues exceeding EUR 260M, Er-Kim is not just a partner but a trailblazer in healthcare, continually setting new standards in commercialization and patient access. For more information, please visit http://www.er-kim.com/. About Puma Biotechnology Puma Biotechnology, Inc. is a biopharmaceutical company with a focus on the development and commercialization of innovative products to enhance cancer care. Puma in-licensed the global development and commercialization rights to PB272 (neratinib, oral) in 2011. Neratinib, oral was approved by the U.S. Food and Drug Administration in 2017 for the extended adjuvant treatment of adult patients with early- stage HER2-overexpressed/amplified breast cancer, following adjuvant trastuzumab-based therapy, and is marketed in the United States as NERLYNX® (neratinib) tablets. In February 2020, NERLYNX was also approved by the FDA in combination with capecitabine for the treatment of adult patients with advanced or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting. NERLYNX was granted marketing authorization by the European Commission in 2018 for the extended adjuvant treatment of adult patients with early stage hormone receptor-positive HER2-overexpressed/amplified breast cancer and who are less than one year from completion of prior adjuvant trastuzumab-based therapy. NERLYNX® is a registered trademark of Puma Biotechnology, Inc. Further information about Puma Biotechnology may be found at https://www.pumabiotechnology.com. In September 2022, Puma entered into an exclusive license agreement for the development and commercialization of the anti-cancer drug alisertib, a selective, small molecule, orally administered inhibitor of aurora kinase A. Initially, Puma intends to focus the development of alisertib on the treatment of small cell lung cancer and breast cancer. In February 2024, Puma initiated ALISCA™-Lung1, a Phase II clinical trial of alisertib monotherapy for the treatment of patients with extensive-stage small cell lung cancer. In November 2024, Puma initiated ALISCA™-Breast1, a Phase II clinical trial of alisertib in combination with endocrine therapy for the treatment of patients with HER2-negative, HR-positive metastatic breast cancer. Media contact: Rosalia ScampoliMarketcom PRTel: (914) 815-1465rscampoli@marketcompr.com

上市批准引进/卖出临床2期

2025-04-28

·investor.pumabiotechnology.com

Puma Biotechnology Presents Clinical Data on Neratinib at the AACR Annual Meeting 2025

LOS ANGELES--(BUSINESS WIRE)-- Puma Biotechnology, Inc. (NASDAQ: PBYI), a biopharmaceutical company, announced that clinical data on neratinib were presented in a poster session at the American Association for Cancer Research (AACR) Annual Meeting 2025. The AACR Annual Meeting is currently taking place at the McCormick Place in Chicago, Illinois. The poster is entitled, “CT071: Phase I trial of trastuzumab deruxtecan in combination with neratinib in solid tumors with HER2 alterations (NCI 10495).” Andrew A. Davis, Assistant Professor at Washington University School of Medicine, presented the poster during Session PO.CT01.01 – First-in-Human Phase I Clinical Trials 1. NCI 10495 is sponsored by the National Cancer Institute, part of National Institutes of Health, and conducted in the NCI funded Experimental Therapeutics Clinical Trials Network (ETCTN). This open label, multi-center, Phase I clinical trial (NCT05372614) enrolled 20 patients in three cohorts treated with three increasing dose levels, or a 3+3 trial design, to evaluate the safety and tolerability of trastuzumab deruxtecan (T-DXd or ENHERTU®) in combination with neratinib (NERLYNX®). Eligible patients had advanced solid tumors with HER2 immunohistochemistry 3+ (IHC3+), HER2 amplification identified by in situ hybridization or next-generation sequencing, or an activating HER2 mutation. Prior treatment with trastuzumab deruxtecan was not allowed. The dose of trastuzumab deruxtecan was fixed at 5.4 mg/kg. The three dose levels (DLs) for neratinib all started at 120 mg daily for the first week. DL1 remained at 120 mg daily throughout the course of treatment, DL2 escalated to 160 mg daily in week 2 and 200 mg by week 3, and DL3 escalated to 160 mg in week 2 and 240 mg by week 3. The primary endpoints were the determination of the dose-limiting toxicities (DLTs) during the first two cycles of treatment (42 days) and the determination of the recommended Phase II dose of the combination of trastuzumab deruxtecan and neratinib. Twenty patients received study treatment (DL1 N=7, DL2 N=4, and DL3 N=9). The most common treatment-emergent adverse events of any grade included nausea (N=15, 75%), diarrhea (N=15, 75%), fatigue (N=13, 65%), and hypokalemia (N=11, 55%). Grade 3 treatment-emergent adverse events that occurred in more than 2 patients included anemia (N=6, 30%), diarrhea (N=4, 20%), and hypokalemia (N=3, 15%). The only Grade 4 treatment-related adverse event was neutropenia that occurred in 1 patient (5%). One DLT (acute kidney injury) was observed at DL1, 0 DLTs were observed in DL2, and 1 DLT was observed (fatigue leading to early drug discontinuation) at DL3. Three patients developed Grade 1 pneumonitis or interstitial lung disease (ILD), 2 at DL1 and 1 at DL3. The proportion of reported treatment-emergent adverse events was lower at higher dose levels. Of 15 response-evaluable patients by RECIST v1.1, 4 patients had a partial response (PR), including patients with gastroesophageal (N=2, one HER2 IHC 3+ and one HER2 mutated), pancreatic (N=1, IHC 3+), and ovarian (N=1, IHC 3+; unconfirmed response) cancers. Notably, 3 of 5 patients with advanced pancreatic cancer were observed to have tumor regression (1 PR for 13+ cycles, 2 with stable disease consisting of one patient with -29.4% tumor regression for 9 cycles and one patient with -13.3% tumor regression for 8 cycles). Dose level 3, which consisted of trastuzumab deruxtecan at 5.4 mg/kg and neratinib at 120 mg in week 1, 160 mg week 2, and 240 mg week 3 onward, was selected as the recommended Phase II dose. Part 2 of this study, which consists of a pharmacodynamic evaluation of trastuzumab deruxtecan (5.4 mg/kg) and neratinib (RPD2) in 12 patients, opened to enrollment in March 2025. Patients with any advanced solid tumor and HER2 amplification/overexpression or a HER2 mutation will be enrolled. “Neratinib and trastuzumab deruxtecan showed impressive combination activity in preclinical models of HER2-mutated breast cancers, which prompted evaluation of the combination in this first-in-human clinical trial. I am pleased to report that the combination not only had a manageable safety profile, but we also observed early signs of efficacy across a variety of HER2-altered tumors,” said Dr. Davis. Alan H. Auerbach, Chief Executive Officer and President of Puma Biotechnology, added, “We are pleased with the tolerability and potentially promising signals of efficacy of neratinib in combination with trastuzumab deruxtecan, especially in hard-to-treat tumors including pancreatic cancer. We look forward to continued evaluation of this combination in the Phase II portion of this study.” NCI 10495 is also supported by Puma Biotechnology and Daiichi Sankyo, Inc. through Cooperative Research and Development Agreements with NCI. Trastuzumab deruxtecan is a specifically engineered HER2 directed DXd antibody drug conjugate (ADC) discovered by Daiichi Sankyo (TSE: 4568) and being jointly developed and commercialized by Daiichi Sankyo and AstraZeneca (LSE/STO/Nasdaq: AZN). About Puma Biotechnology Puma Biotechnology, Inc. is a biopharmaceutical company with a focus on the development and commercialization of innovative products to enhance cancer care. Puma in-licensed the global development and commercialization rights to PB272 (neratinib, oral) in 2011. Neratinib, oral was approved by the U.S. Food and Drug Administration in 2017 for the extended adjuvant treatment of adult patients with early stage HER2-overexpressed/amplified breast cancer, following adjuvant trastuzumab-based therapy, and is marketed in the United States as NERLYNX® (neratinib) tablets. In February 2020, NERLYNX was also approved by the FDA in combination with capecitabine for the treatment of adult patients with advanced or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting. NERLYNX was granted marketing authorization by the European Commission in 2018 for the extended adjuvant treatment of adult patients with early stage hormone receptor-positive HER2-overexpressed/amplified breast cancer and who are less than one year from completion of prior adjuvant trastuzumab-based therapy. NERLYNX® is a registered trademark of Puma Biotechnology, Inc. In September 2022, Puma entered into an exclusive license agreement for the development and commercialization of the anti-cancer drug alisertib, a selective, small molecule, orally administered inhibitor of aurora kinase A. Initially, Puma intends to focus the development of alisertib on the treatment of small cell lung cancer and breast cancer. In February 2024, Puma initiated ALISCA™-Lung1, a Phase II clinical trial of alisertib monotherapy for the treatment of patients with extensive-stage small cell lung cancer. In November 2024, Puma initiated ALISCA™-Breast1, a Phase II clinical trial of alisertib in combination with endocrine therapy for the treatment of patients with HER2-negative, HR-positive metastatic breast cancer. Further information about Puma Biotechnology may be found at https://www.pumabiotechnology.com. Alan H. Auerbach or Mariann Ohanesian, Puma Biotechnology, Inc., +1 424 248 6500 info@pumabiotechnology.com ir@pumabiotechnology.com David Schull or Olipriya Das, Russo Partners, +1 212 845 4200 david.schull@russopartnersllc.com olipriya.das@russopartnersllc.com

临床1期临床结果引进/卖出临床2期上市批准

2025-03-14

·学术经纬

《细胞》子刊：利用新型降解剂治疗神经母细胞瘤

撰文 | 冉茂双责编 | 周叶斌 MYCN的异常表达与多种人类癌症的肿瘤发生密切相关，其中MYCN扩增是高危神经母细胞瘤 (NB) 的主要遗传驱动因素，也是临床上最强的独立不良预后因素。MYCN基因编码致癌转录因子N-Myc在正常神经前体细胞中泛素化-蛋白酶体系统快速降解，在MYCN扩增的NB细胞中，Aurora-A激酶与SCF-Fbxw7 E3连接酶复合体结合，干扰泛素化，导致N-Myc稳态蛋白水平升高，从而促进肿瘤生长。尽管Aurora-A变构抑制剂 (如MLN8237) 可破坏Aurora-A/N-Myc复合物，但其对N-Myc的作用存在负协同效应，临床疗效有限。另一策略则是通过Aurora-A降解剂促进N-Myc降解，蛋白降解靶向嵌合体 (PROTAC) 技术可以通过双功能配体将泛素连接酶E3和靶标蛋白连接成三体复合体，进而利用“泛素-蛋白酶体”途径特异性地降解靶蛋白，可以改善“不可成药”靶点的成药性。通过该技术选择性降解Aurora-A，可为N-Myc高表达患者提供新的治疗方案。近日，Daniel A. Harki 团队在 Cell Chemical Biology 发表题为 Targeting N-Myc in neuroblastoma with selective Aurora kinase A degraders 的研究论文中，作者开发了一种选择性Aurora-A降解剂HLB-0532259能够靶向诱导N-Myc降解，并在治疗MYCN扩增的神经母细胞瘤方面展现出良好的疗效。敲低Aurora-A表达可显著下调MYCN扩增型神经母细胞瘤中的N-Myc水平。因此，可以通过化学手段靶向降解Aurora-A来降解破坏N-Myc。研究人员通过PROTAC技术开发了Aurora-A降解剂，以促进N-Myc的降解。研究人员选择FDA已批准药物瑞博西利 (Ribociclib, 一种高度选择性的CDK4/6抑制剂) ，通过对其吡啶基哌嗪部分进行化学修饰，生成的配体2对Aurora A的结合亲和力增加了约1000倍；进一步，将配体2与沙利度胺(Thalidomide, 靶向CRBN，CRL4CRBN E3泛素连接酶的底物受体) 通过6碳烷基链连接，开发出了针对Aurora-A的蛋白降解嵌合体配体4，命名为HLB-0532259；同时根据两种药物分子特性生成对照配体3、5和6。对468个激酶在1 μM浓度下的筛选结果也显示HLB-0532259具有优异的靶点选择性。图1. Aurora-A激酶选择性降解剂设计开发。A 表示通过靶向Aurora-A (AURKA) 蛋白质降解实现N-Myc降解示意图。B 显示了对CDK4/6抑制剂1 (Ribociclib) 进行化学修饰，合成Aurora-A配体2和3，以及Aurora-A 的蛋白降解嵌合体分子4、5和6。C 显示了Aurora-A配体对Aurora-A和CDK4-Cyclin D1的结合亲和力 (KD) 。D 显示了配体4对468种激酶的选择性分布图。E 显示配体4诱导MCF-7细胞中Aurora-A而非CDK4的降解。F 显示了配体4在MCF-7细胞中诱导Aurora-A降解的机制通过蛋白酶体降解途径。 HLB-0532259在MYCN扩增的神经母细胞瘤细胞中选择性促进Aurora-A和N-Myc的降解。研究证实，该降解剂通过泛素-蛋白酶体途径发挥作用，其降解效果优于MLN8237和CD532等抑制剂。其高选择性体现在对其他蛋白影响较小，尤其是已知CRBN调节剂的底物如GSPT1、CK1a和ZFP91。这些结果表明HLB-0532259在Aurora-A和N-Myc选择性降解方面具有显著优势。图2. HLB-0532259间接诱导MYCN扩增的NB细胞中N-Myc降解。A-D 结果显示在SK-N-BE(2)细胞中时间依赖性地诱导Aurora-A和N-Myc降解及其降解曲线。E 显示HLB-0532259诱导Aurora-A和N-Myc降解依赖泛素-蛋白酶体途径。F 结果显示HLB-0532259在SK-N-BE(2)和IMR-32细胞中并未影响MYCN mRNA水平，表明N-Myc蛋白水平的下降并非由于其转录抑制。G-H 表明与选择性USP7抑制剂FT671的联合治疗显示出协同降解N-Myc的效果，表明USP7对多聚泛素化N-Myc具有拯救作用。I 结果显示HLB-0532259与MLN8237和CD532比较具有更好的降解效果。进一步的体内外实验表明，HLB-0532259对MYCN扩增的神经母细胞瘤具有显著治疗潜力。HLB-0532259处理显著影响了p53和N-Myc通路，导致MYCN扩增的NB细胞周期停滞和凋亡。在体外实验中，HLB-0532259对MYCN扩增的NB细胞表现出显著的抑制作用，而对MYCN非扩增的NB细胞效果较弱。此外，HLB-0532259在小鼠模型中也表现出抗肿瘤活性，能够显著延缓肿瘤生长，在初始治疗第9天时观察到肿瘤体积的显著减少。然而，长期使用可能导致肠道坏死等副作用，这可能与其较长的半衰期和较高的药物暴露有关。这些结果为未来优化HLB-0532259的理化和药代动力学特性以提高其治疗效果提供了基础。图3. HLB-0532259在神经母细胞瘤治疗中的作用及其机制。A 显示了SK-N-BE(2)细胞在HLB-0532259后蛋白质丰度的变化情况。B 显示SK-N-BE(2)和Kelly细胞在HLB-0532259，Aurora-A、N-Myc及其他激酶的蛋白表达情况。C-D 显示HLB-0532259处理TP53野生型IMR-32细胞中，上调了肿瘤抑制蛋白p53和p21Cip1的表达，下调了致癌蛋白N-Myc和CyclinDs表达。E 显示了HLB-0532259处理IMR-32细胞后凋亡标志物裂解的PARP-1和激活型caspase-3表达。F-G 分别显示了HLB-0532259在SK-N-BE(2)和IMR-32细胞中的细胞毒性，以及在MYCN扩增和MYCN非扩增的NB细胞中的细胞毒性。H 显示了HLB-0532259在小鼠中通过腹腔注射后的药代动力学特性。I-J 显示了HLB-0532259每2天或每3天腹腔注射对雌性裸鼠中SK-N-BE(2)肿瘤生长的影响。综上，该研究开发的靶向Aurora-A蛋白降解嵌合分子HLB-0532259，可以间接诱导N-Myc的降解，并且有高度的降解选择性，并在体外和体内NB模型中表现出靶向调节效应和治疗潜力。但未来还需要进一步研究HLB-0532259诱导N-Myc降解的分子机制以及药物化学工作来优化和改善其药物样性质。撰文责编制作排版 | 车洁校对 | uu 延伸阅读神经母细胞瘤最新综述：发病机制分析如何推进前沿治疗发展？神经母细胞瘤的新靶点及优先开发药物列表 *本文由深圳市拾玉儿童公益基金会“儿童肿瘤前沿”团队编译或约稿，文中图表均源引自文献原文。本文著作权归文章作者所有，欢迎个人转发分享，未经允许禁止转载，作者拥有所有法定权利，违者必究。如需转载，请留言或联系shiyu@curekids.cn。本文旨在分享儿童肿瘤科研前沿成果，不是治疗方案推荐。如需获得疾病治疗方案指导，请前往正规医院就诊。 ▼滑动查看更多▼ 原文摘要（Abstract） The N-Myc transcription factor, encoded by MYCN, is a mechanistically validated, yet challenging, target for neuroblastoma (NB) therapy development. In normal neuronal progenitors, N-Myc undergoes rapid degradation, while, in MYCN-amplified NB cells, Aurora kinase A (Aurora-A) binds to and stabilizes N-Myc, resulting in elevated protein levels. Here, we demonstrate that targeted protein degradation of Aurora-A decreases N-Myc levels. A potent Aurora-A degrader, HLB-0532259 (compound 4), was developed from an Aurora-A-binding ligand that engages the Aurora-A/N-Myc complex. HLB-0532259 promotes the degradation of Aurora-A, which elicits concomitant N-Myc degradation, with nanomolar potency and excellent selectivity. HLB-0532259 surpasses the cellular efficacy of established allosteric Aurora-A inhibitors, exhibits favorable pharmacokinetic properties, and elicits tumor reduction in a murine xenograft NB model. This study broadly delineates a strategy for targeting "undruggable" proteins that are reliant on accessory proteins for cellular stabilization. DOI: 10.1016/j.chembiol.2024.12.006. 👇点击此处，直达原文

AACR会议临床结果蛋白降解靶向嵌合体临床1期

100 项与 Alisertib 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D10085	Alisertib	-	DB05220

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
难治性外周T细胞淋巴瘤	临床3期	美国	Millennium Pharmaceuticals, Inc.	2012-06-11
难治性外周T细胞淋巴瘤	临床3期	澳大利亚	Millennium Pharmaceuticals, Inc.	2012-06-11
难治性外周T细胞淋巴瘤	临床3期	奥地利	Millennium Pharmaceuticals, Inc.	2012-06-11
难治性外周T细胞淋巴瘤	临床3期	白俄罗斯	Millennium Pharmaceuticals, Inc.	2012-06-11
难治性外周T细胞淋巴瘤	临床3期	比利时	Millennium Pharmaceuticals, Inc.	2012-06-11
难治性外周T细胞淋巴瘤	临床3期	巴西	Millennium Pharmaceuticals, Inc.	2012-06-11
难治性外周T细胞淋巴瘤	临床3期	保加利亚	Millennium Pharmaceuticals, Inc.	2012-06-11
难治性外周T细胞淋巴瘤	临床3期	加拿大	Millennium Pharmaceuticals, Inc.	2012-06-11
难治性外周T细胞淋巴瘤	临床3期	智利	Millennium Pharmaceuticals, Inc.	2012-06-11
难治性外周T细胞淋巴瘤	临床3期	捷克	Millennium Pharmaceuticals, Inc.	2012-06-11

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临床结果

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分期

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT06369285 (ALISCA-Breast1, ESMO_BC2025)	临床2期	HR阳性/HER2阴性乳腺癌 Aurora kinase A (AURKA)	-	Alisertib 30 mg + Endocrine Therapy	繭夢壓壓簾築製鏇壓廠(壓膚築範糧襯襯鏇鹽淵) = 夢網獵鏇窪鹽艱鹽鏇網遞築壓繭糧選艱築繭觸 (願鑰鹽鏇鹹蓋窪觸壓膚 ) 更多	积极	2025-05-14
				Alisertib 40 mg + Endocrine Therapy	繭夢壓壓簾築製鏇壓廠(壓膚築範糧襯襯鏇鹽淵) = 遞遞蓋鏇選顧範蓋積願遞築壓繭糧選艱築繭觸 (願鑰鹽鏇鹹蓋窪觸壓膚 ) 更多
NCT02860000 (TBCRC041, CTgov)	临床2期	局部晚期乳腺癌 \| 转移性乳腺癌 \| 激素难治性乳腺癌 ... 更多	96	Laboratory Biomarker Analysis+Alisertib (Arm I (Alisertib))	憲襯艱膚鹽糧夢淵鏇願(鬱築齋積繭製廠選選餘) = 鹹廠製觸築鏇淵齋壓衊艱獵蓋觸遞鏇衊窪膚夢 (構繭淵齋夢憲鏇夢製壓, 夢遞壓醖範願範鹹廠鏇 ~ 築齋鏇醖範糧積鹽艱鹽) 更多	-	2024-10-18
				Laboratory Biomarker Analysis+Alisertib+Fulvestrant (Arm II (Alisertib, Fulvestrant))	憲襯艱膚鹽糧夢淵鏇願(鬱築齋積繭製廠選選餘) = 範範獵構網夢簾鹽衊遞艱獵蓋觸遞鏇衊窪膚夢 (構繭淵齋夢憲鏇夢製壓, 構鹽網壓獵淵願憲鹽膚 ~ 餘壓襯餘壓築積襯蓋襯) 更多
NCT02187991 (CTgov)	临床2期	转移性乳腺癌	169	Paclitaxel (ER+/HER2- Paclitaxel Alone)	艱鏇憲遞醖齋襯選鹹鬱(蓋衊鬱夢積繭鏇廠糧餘) = 餘觸夢構簾鬱顧壓窪淵繭糧築窪構製顧糧廠網 (憲願選齋繭醖壓獵齋獵, 簾窪夢醖夢遞範範醖糧 ~ 蓋製夢齋餘繭網蓋艱築) 更多	-	2024-10-09
				Alisertib+Paclitaxel (ER+/HER2- Paclitaxel Plus Alisertib)	艱鏇憲遞醖齋襯選鹹鬱(蓋衊鬱夢積繭鏇廠糧餘) = 選遞製壓襯窪鏇壓製製繭糧築窪構製顧糧廠網 (憲願選齋繭醖壓獵齋獵, 鹽窪糧鹽餘網齋構觸簾 ~ 顧簾顧築鏇願積顧簾壓) 更多
NCT04085315 (phase I/Ib study, ASCO2024) 人工标引	临床1期	EGFR突变肺癌 EGFR	21	alisertib+osimertinib	範遞鑰鹽觸齋製願選觸(繭鑰鏇壓憲鑰淵製積壓) = neutropenia (42.9%), anemia (42.9%), and diarrhea (38.1%) 獵齋構餘糧膚壓膚積繭 (觸網鏇膚範夢繭醖獵衊 )	积极	2024-05-24
NCT02860000 (TBCRC041, ASCO2024)	临床2期	转移性乳腺癌 ESR1 \| PIK3CAmutation \| AKT1 ... 更多	91	Alisertib + Fulvestrant	築襯夢鏇範壓糧鑰艱願(衊鬱憲壓簾觸鏇鬱築齋): HR = 1.8 (95% CI, 1.1 ~ 2.9), P-Value = 0.014	积极	2024-05-24
				Alisertib
NCT02187991 (ASCO2023) 人工标引	临床2期	转移性三阴性乳腺癌 \| HR阳性/HER2阴性乳腺癌 Hormone Receptor Positive \| PR Negative \| ER Negative \| ... 更多	96	alisertib (A) combined with paclitaxel (P) or P alone	齋鬱製蓋膚鏇鹽網鑰範(網築糧積構膚醖糧夢餘) = 願顧壓廠壓鏇鬱鑰選膚鬱鹽築鹽願鬱鬱蓋網鏇 (艱遞蓋憲顧糧壓構顧醖 )	积极	2023-05-31
NCT02860000 (Pubmed)	临床2期	晚期乳腺癌 CDK 4/6i	91	Alisertib	積範膚衊蓋構膚衊夢獵(鬱網艱鹹艱積衊網鏇淵) = 醖觸網餘製觸糧顧積醖壓餘範顧鬱顧衊廠簾醖 (製窪範顧製鹽糧鑰窪鬱, 29.0% ~ 54.5%) 更多	-	2023-03-09
				Alisertib + Fulvestrant	積範膚衊蓋構膚衊夢獵(鬱網艱鹹艱積衊網鏇淵) = 糧襯選遞餘膚餘窪繭膚壓餘範顧鬱顧衊廠簾醖 (製窪範顧製鹽糧鑰窪鬱, 18.0% ~ 42.0%) 更多
NCT02293005 (CTgov)	临床2期	不可切除的胸膜恶性间皮瘤 \| 恶性间皮瘤 \| 肺癌	28	Alisertib	範艱選網範齋廠淵積憲 = 鏇糧憲鬱齋齋壓膚獵艱襯衊窪顧艱膚遞廠鑰鹽 (齋願襯顧獵製鏇艱醖獵, 選餘製觸艱構繭憲膚築 ~ 衊膚艱壓齋壓襯築願鹹) 更多	-	2022-10-04
NCT01924260 (Pubmed) 人工标引	临床1期	HR阳性/HER2低表达实体瘤 \| 胰腺癌	26	Alisertib+Gemcitabine	淵艱醖積簾鏇簾艱蓋鬱(壓選遞齋鬱窪製遞鹹鹽) = 製觸構壓願鬱構構襯壓廠構鹹簾鏇艱範鬱築襯 (觸網築築艱衊顧遞艱窪, 2.1 ~ 4.5) 更多	积极	2022-07-30
NCT02114229 (SJATRT, Pubmed) 人工标引	临床2期	中枢神经系统横纹肌瘤	30	alisertib	製網觸獵繭壓夢築憲鬱(淵壓鹽夢齋糧願範願餘) = 廠醖選餘築願製鏇醖壓範積構憲餘衊遞襯淵餘 (遞憲鏇衊醖鏇築壓製艱, 5.6) 更多	不佳	2022-06-02