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更新于：2026-04-09
Tersolisib
更新于：2026-04-09
概要
基本信息
药物类型 小分子化药 |
别名 STX-H1047-PI3Ka inhibitors (Scorpion Therapeutics)、LY4064809、ST-814 + [2] |
作用方式 抑制剂 |
作用机制 PIK3CA H1047R 抑制剂(PIK3CA H1047R突变 抑制剂)、PIK3CA H1047X 抑制剂(磷脂酰肌醇3-激酶α突变型H1047X 抑制剂) |
在研适应症 |
非在研适应症- |
非在研机构- |
最高研发阶段临床3期 |
首次获批日期- |
最高研发阶段(中国)临床3期 |
特殊审评- |
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结构/序列
分子式C16H12F5N5O2 |
InChIKeyLGPNQALKGDDVBD-CYBMUJFWSA-N |
CAS号2883540-92-7 |
关联
6
项与 Tersolisib 相关的临床试验NCT07339735
A Phase 1, Open-Label Study to Assess the Relative Bioavailability of Two LY4064809 Formulations in Healthy Adult Participants
NCT07174336
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of LY4064809 Combined With a CDK4/6 Inhibitor and Endocrine Therapy in Adults With HR+, HER2-Advanced Breast Cancer With a PIK3CA Mutation Who Received No Prior Treatment for Advanced Breast Cancer (PIKALO-2)
NCT07247357
A Phase 1, Open-Label Study of the Pharmacokinetics of LY4064809 in Healthy Adult Chinese Participants
100 项与 Tersolisib 相关的临床结果
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100 项与 Tersolisib 相关的转化医学
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100 项与 Tersolisib 相关的专利（医药）
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7
项与 Tersolisib 相关的文献（医药）2026-01-23Annual Review of Pharmacology and Toxicology
Structural Insights into the Development of Inhibitors Against Cancer-Specific Mutations of PI3Kα
Review
作者: Liu, Xiao ; Chen, Yan ; Feng, Wenbo ; Zhou, Qingtong ; Chen, Yanyan ; Han, Wei ; Wang, Ming-Wei
Phosphoinositide 3-kinase alpha (PI3Kα) is a pivotal regulator of cell growth, proliferation, and survival. Dysregulation of the PI3K/AKT/mTOR pathway, driven predominantly by
PIK3CA
mutations (e.g., H1047R, E542K, and E545K), is a hallmark of many cancers. Advances in structural, biochemical, and computational studies have elucidated mutation-specific conformational changes of PI3Kα. While early pan- and isoform-selective PI3K inhibitors (alpelisib) show clinical utility, their intrinsic toxicity and resistance to treatment persist. Recent breakthroughs include the emergence of allosteric inhibitors (RLY-2608 and STX-478) that exploit mutation-induced cryptic pockets to achieve mutant selectivity as well as covalent inhibitors and degraders (inavolisib) that enhance specificity, aiming at decoupling antitumor activity from metabolic dysfunction. This review synthesizes current progress in PI3Kα inhibitor development, emphasizing structural characteristics, clinical challenges, and emerging strategies. Addressing challenges to increase mutant selectivity, exploring conformational modulation, uncovering new mechanisms of action, and implementing personalized therapies are key future directions for PI3Kα-targeted drug discovery.
2025-08-10BRITISH JOURNAL OF CANCER
Multi-node inhibition targeting mTORC1, mTORC2 and PI3Kα potently inhibits the PI3K/AKT/mTOR pathway in endometrial and breast cancer models
Article
作者: Mukherjee, Siddhartha ; Cantley, Lewis C ; Maddocks, Oliver D K ; Goncalves, Marcus D ; Tyrakis, Petros A ; Kampjut, Domen ; Lindström, H Jonathan G ; Hopkins, Benjamin D ; Chirnomas, Deborah ; Steele, Georgina F
Abstract:
Background:
While PI3K/AKT/mTOR signalling plays a critical role in cancer, targeting this pathway with single node inhibitors has limited efficacy due to several known factors such as pathway feedback reactivation, co-occurring pathway mutations, and systemic glucose dysregulation leading to hyperinsulinemia. While multi-node inhibition approaches have shown promising clinical efficacy, they require further mechanistic characterisation.
Methods:
Using models of endometrial and breast cancer, we evaluated the efficacy of a multi-node PI3K/AKT/mTOR pathway inhibitor approach utilising the dual mTORC1/mTORC2 inhibitor sapanisertib, PI3Kα inhibitor serabelisib and an insulin-supressing diet. Pathway signalling inhibition versus a range of single-node inhibitors was measured via S6, AKT and 4E-BP1 phosphorylation.
Results:
The serabelisib-sapanisertib combination more effectively suppressed PI3K/AKT/mTOR pathway signalling, particularly 4E-BP1, than single-node inhibitors, including alpelisib, capivasertib, inavolisib, everolimus and mutant-specific PI3K inhibitors RLY-2608 and STX-478. Serabelisib plus sapanisertib combined effectively with a range of other therapeutics, such as chemotherapies, hormone targeted therapies and CDK4/6 inhibitors. In xenograft models, sapanisertib, serabelisib plus paclitaxel/insulin supressing diet achieved complete inhibition of tumour growth/tumour regression.
Conclusion:
Multi-node PI3K/AKT/mTOR pathway inhibition with serabelisib, sapanisertib and ISD is highly effective in preclinical models of endometrial and breast cancer, supporting continued clinical development in these and other solid tumours.
2024-12-01Computational and Structural Biotechnology Journal
Free energy landscape of the PI3Kα C-terminal activation
Article
作者: Burke, John E ; Papadourakis, Michail ; Cournia, Zoe ; Kotzampasi, Danai Maria ; Burke, John E.
The gene PIK3CA, encoding the catalytic subunit p110α of PI3Kα, is the second most frequently mutated gene in cancer, with the highest frequency oncogenic mutants occurring in the C-terminus of the kinase domain. The C-terminus has a dual function in regulating the kinase, playing a putative auto-inhibitory role for kinase activity and being absolutely essential for binding to the cell membrane. However, the molecular mechanisms by which these C-terminal oncogenic mutations cause PI3Kα overactivation remain unclear. To understand how a spectrum of C-terminal mutations of PI3Kα alter kinase activity compared to the WT, we perform unbiased and biased Molecular Dynamics simulations of several C-terminal mutants and report the free energy landscapes for the C-terminal "closed-to-open" transition in the WT, H1047R, G1049R, M1043L and N1068KLKR mutants. Results are consistent with HDX-MS experimental data and provide a molecular explanation why H1047R and G1049R reorient the C-terminus with a different mechanism compared to the WT and M1043L and N1068KLKR mutants. Moreover, we show that in the H1047R mutant, the cavity, where the allosteric ligands STX-478 and RLY-2608 bind, is more accessible contrary to the WT. This study provides insights into the molecular mechanisms underlying activation of oncogenic PI3Kα by C-terminal mutations and represents a valuable resource for continued efforts in the development of mutant selective inhibitors as therapeutics.
100 项与 Tersolisib 相关的药物交易
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研发状态
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| 适应症 | 最高研发状态 | 国家/地区 | 公司 | 日期 |
|---|---|---|---|---|
| PIK3CA突变/HR阳性/HER2阴性乳腺癌 | 临床3期 | 美国 | 2026-01-09 | |
| PIK3CA突变/HR阳性/HER2阴性乳腺癌 | 临床3期 | 中国 | 2026-01-09 | |
| 晚期乳腺癌 | 临床3期 | 美国 | 2025-12-22 | |
| 晚期乳腺癌 | 临床3期 | 中国 | 2025-12-22 | |
| 晚期乳腺癌 | 临床3期 | 日本 | 2025-12-22 | |
| 晚期乳腺癌 | 临床3期 | 阿根廷 | 2025-12-22 | |
| 晚期乳腺癌 | 临床3期 | 澳大利亚 | 2025-12-22 | |
| 晚期乳腺癌 | 临床3期 | 比利时 | 2025-12-22 | |
| 晚期乳腺癌 | 临床3期 | 巴西 | 2025-12-22 | |
| 晚期乳腺癌 | 临床3期 | 加拿大 | 2025-12-22 |
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临床结果
临床结果
适应症
分期
评价
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临床1/2期 | 晚期恶性实体瘤 PIK3CA mutations | HR+ | HER2- | 204 | 夢艱製選窪憲鬱選遞艱(鹹遞獵蓋襯簾製鬱簾醖) = 鹹壓繭糧齋製餘選鹹願 淵夢繭襯糧鹹窪範壓簾 (範膚觸壓觸膚夢鹽顧襯 ) 更多 | 积极 | 2025-10-17 | ||
夢艱製選窪憲鬱選遞艱(鹹遞獵蓋襯簾製鬱簾醖) = 願選鏇襯淵顧願選鬱顧 淵夢繭襯糧鹹窪範壓簾 (範膚觸壓觸膚夢鹽顧襯 ) 更多 | |||||||
临床1/2期 | 晚期恶性实体瘤 PI3Kαm | 61 | 積醖鬱糧遞構餘齋簾鏇(淵壓選範蓋觸夢鏇廠願) = 鏇遞鏇選壓鏇壓構淵範 壓網網積遞鹹鹽構壓選 (積鹹鬱夢蓋觸鹽獵範簾 ) 更多 | 积极 | 2024-09-15 | ||
(HR+/HER2- BC) | 壓積襯襯願構夢製網齋(構選齋淵繭膚襯醖鬱鹽) = 廠膚鏇顧齋鑰憲繭築餘 憲觸憲構範鹹憲觸鏇齋 (淵鑰鹽獵積獵選鏇遞窪 ) |
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