Pictilisib(Pictilisib) - 药物靶点：PI3Kα x PI3Kδ_在研适应症：乳腺癌，胃肠道肿瘤，黑色素瘤_专利_临床

概要

基本信息

药物类型

小分子化药

别名

Pictilisib (USAN)、Pictrelisib

+ [2]

靶点

PI3Kα x PI3Kδ

作用机制

PI3Kα抑制剂(磷脂酰肌醇3-激酶α抑制剂)、PI3Kδ抑制剂(磷脂酰肌醇-3激酶δ抑制剂)

治疗领域

肿瘤免疫系统疾病心血管疾病+ [5]

在研适应症

乳腺癌胃肠道肿瘤黑色素瘤+ [2]

非在研适应症

晚期乳腺癌晚期恶性实体瘤复发性乳腺癌+ [15]

原研机构

Genentech, Inc.

在研机构

The Institute of Cancer Research: Royal Cancer Hospital

非在研机构

Genentech, Inc.

最高研发阶段临床2期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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结构/序列

分子式C23H27N7O3S2

InChIKeyLHNIIDJUOCFXAP-UHFFFAOYSA-N

CAS号957054-30-7

关联

19

项与 Pictilisib 相关的临床试验

NCT02389842

/ Completed临床1期IIT

PIPA: a Phase Ib Study to Assess the Safety, Tolerability and Efficacy of the PI3K Inhibitors, Taselisib (GDC-0032) or Pictilisib (GDC-0941), in Combination with PAlbociclib, with the Subsequent Addition of Fulvestrant in PIK3CA-mutant Breast Cancers

Part A: This is a phase Ib trial combining the CDK4/6 inhibitor palbociclib with the PI3K inhibitors taselisib, or pictilisib. There are two treatment arms during the dose escalation phase where patients will receive either taselisib OR pictilisib in combination with palbociclib. Palbociclib, taselisib and pictilisib can all be given orally once daily with food, in a 21-days-on and 7-days-off schedule. Once the MTD is reached, the combination with the optimum safety and PK/PD profile will be taken forward to the dose expansion phase (Part B).
Part B1: At the MTD dose expansion, fulvestrant will be administered in addition to palbociclib and taselisib or pictilisib orally once daily, in a 21-days-on and 7-days-off schedule in the ER+ve HER2-ve PIK3CA mutant breast cancer cohort. Fulvestrant will be given intramuscularly on Day 1, Day 15 in cycle one followed by Day 1 for all subsequent cycles.
Part B2: At the MTD dose expansion, patients with PIK3CA mutant advanced solid tumours will be treated with palbociclib and taselisib or pictilisib orally once daily, in a 21-days-on and 7-days-off schedule.

开始日期2015-03-25

申办/合作机构

Royal Marsden NHS Foundation Trust

[+3]

NCT02092831

/ Completed临床1期

A PHASE 1, OPEN-LABEL STUDY TO EVALUATE THE EFFECT OF FORMULATION AND TABLET HARDNESS ON THE RELATIVE BIOAVAILABILITY OF PICTILISIB (GDC-0941) IN HEALTHY SUBJECTS

This Phase 1, open-label, randomized, 4-period crossover study is designed to determine the relative bioavailability of GDC-0941 administered as a single dose of the market image formulation at 3 different hardnesses (hardness 1, 2, and 3) and as a single dose of the Phase 2 formulation to healthy male and female volunteers. Participants will be randomly assigned to 4 possible treatment sequences, each comprising 4 periods (1 per formulation), and GDC-0941 will be administered based on the assigned sequence. The study is expected to last 8 weeks.

开始日期2014-04-01

申办/合作机构

Genentech, Inc.

NCT01918306

/ Terminated临床1/2期IIT

A Phase Ib/II Trial of GDC-0941 (a PI3K Inhibitor) in Combination With Cisplatin in Patients With Androgen Receptor Negative Triple Negative Metastatic Breast Cancer

This phase I/II trial study evaluates the tolerability and best tolerated dose of the PI3K inhibitor GDC-0941 when given with the chemotherapy cisplatin. This study will also examine how well the combination of GDC-0941 and cisplatin work in treating patients with androgen receptor negative triple negative metastatic breast cancer. Patients will be randomized to receive cisplatin alone or cisplatin with GDC-0941 in the phase II portion. Those receiving cisplatin alone can receive GDC-0941 upon progression of their disease. Cisplatin is a chemotherapy which has been shown to be effective in treating triple negative breast cancer. Preclinical studies show that adding a PI3K inhibitor such as GDC-0941 to cisplatin may be a more effective treatment for breast cancer.

开始日期2013-09-01

申办/合作机构

The Vanderbilt-Ingram Cancer Center

[+2]

100 项与 Pictilisib 相关的临床结果

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100 项与 Pictilisib 相关的转化医学

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100 项与 Pictilisib 相关的专利（医药）

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264

项与 Pictilisib 相关的文献（医药）

2025-02-01·Bioorganic & Medicinal Chemistry

Exploring the antiproliferative and proapoptotic activities of new pyridopyrimidine derivatives and their analogs

Article

作者: Abou-Seri, Sahar M ; Ali, Hadeer M ; Allam, Shady ; Abdel-Aziz, Hatem A ; Said, Mohamed A

This study investigates a series of newly synthesized compounds, including pyridopyrimidine derivatives (9a-g), tricyclic pyridotriazolopyrimidine analogs (18a-d), and dihydropyrimidinones (22a-i), as apoptotic inducers and inhibitors of phosphatidylinositol-3-kinase α (PI3Kα), with potential anticancer activity. An initial in vitro screening of 60 cancer cell lines identified pyridopyrimidine derivatives 9a-g as promising broad-spectrum anticancer agents, with compound 9e demonstrating the strongest inhibitory activity, particularly against T-47D breast cancer cells. Notably, the antitumor potency of compound 9e surpassed that of Pictilisib, inducing G2-M phase cell cycle arrest and initiating apoptosis through the intrinsic apoptotic pathway. Molecular docking studies further indicated that compound 9e binds to PI3Kα in a similar fashion to the co-crystallized ligand. Moreover, compound 9e exhibited favorable drug-like properties, including compliance with Lipinski's rule and Veber's rule, good solubility, acceptable TPSA, and high gastrointestinal absorption reinforcing its potential as a highly effective anticancer agent.

2024-12-31·Future Science OA

SARS-CoV-2-induced phosphorylation and its pharmacotherapy backed by artificial intelligence and machine learning

Article

作者: Qamar, Fouzia ; Idrees, Jawaria ; Salman, Saad ; Haider, Sana ; Wasim, Asif ; Sharif, Zubair

Aims: To investigate the role of phosphorylation in SARS-CoV-2 infection, potential therapeutic targets and its harmful genetic sequences. Materials & Methods: Data mining techniques were employed to identify upregulated kinases responsible for proteomic changes induced by SARS-CoV-2. Spike and nucleocapsid proteins' sequences were analyzed using predictive tools, including SNAP2, MutPred2, PhD-SNP, SNPs&Go, MetaSNP, Predict-SNP and PolyPhen-2. Missense variants were identified using ensemble-based algorithms and homology/structure-based models like SIFT, PROVEAN, Predict-SNP and MutPred-2. Results: Eight missense variants were identified in viral sequences. Four damaging variants were found, with SNPs&Go and PolyPhen-2. Promising therapeutic candidates, including gilteritinib, pictilisib, sorafenib, RO5126766 and omipalisib, were identified. Conclusion: This research offers insights into SARS-CoV-2 pathogenicity, highlighting potential treatments and harmful variants in viral proteins.

2024-03-22·Oncogene

Simultaneous inhibition of PI3K and PAK in preclinical models of neurofibromatosis type 2-related schwannomatosis

Article

作者: Fernandez-Valle, Cristina ; Nagel, Anna ; Victoria, Berta ; Huegel, Julianne ; Rosario, Rosa ; Hardin, Haley M ; Petrilli, Alejandra

AbstractNeurofibromatosis Type 2 (NF2)-related schwannomatosis is a genetic disorder that causes development of multiple types of nervous system tumors. The primary and diagnostic tumor type is bilateral vestibular schwannoma. There is no cure or drug therapy for NF2. Recommended treatments include surgical resection and radiation, both of which can leave patients with severe neurological deficits or increase the risk of future malignant tumors. Results of our previous pilot high-throughput drug screen identified phosphoinositide 3-kinase (PI3K) inhibitors as strong candidates based on loss of viability of mouse merlin-deficient Schwann cells (MD-SCs). Here we used novel human schwannoma model cells to conduct combination drug screens. We identified a class I PI3K inhibitor, pictilisib and p21 activated kinase (PAK) inhibitor, PF-3758309 as the top combination due to high synergy in cell viability assays. Both single and combination therapies significantly reduced growth of mouse MD-SCs in an orthotopic allograft mouse model. The inhibitor combination promoted cell cycle arrest and apoptosis in mouse merlin-deficient Schwann (MD-SCs) cells and cell cycle arrest in human MD-SCs. This study identifies the PI3K and PAK pathways as potential targets for combination drug treatment of NF2-related schwannomatosis.

1

项与 Pictilisib 相关的新闻（医药）

2024-03-10

·奇点网

基因突变让癌细胞对胰岛素上头，一路追到肝脏。

*仅供医学专业人士阅读参考肝脏作为人体重要的代谢器官，负责生成、接收和整合多种信号，以调节全身葡萄糖或脂肪酸等营养物质的供应。与此同时，肝脏也是黑色素瘤、结肠癌、胰腺癌、乳腺癌等多种癌症的主要转移目标地点。与肺部等其它转移部位相比，肝转移与较差预后以及对免疫检查点阻断等癌症疗法的较低响应率相关。因此，了解肝脏独特的微环境和肝转移的复杂分子机制，有助于开发针对肝转移的有效治疗策略。美国哥伦比亚大学的Benjamin Izar等人发表在《自然·癌症》期刊上的最新研究，找到了驱动癌症肝转移的专属基因变异[1]。Pip4k2c是一种激酶的编码基因，研究者们发现，Pip4k2c缺失突变能够帮助肿瘤细胞更加有效地利用胰岛素来促进自身生长，从而特异性地驱动肿瘤细胞向富含胰岛素的肝脏转移。PI3K抑制剂与SGLT2抑制剂或生酮饮食联合治疗，可以在控制胰岛素水平的同时，减少Pip4k2c缺失介导的肝转移。论文截图为找到肝转移的驱动因素，Benjamin Izar等人利用黑色素瘤小鼠模型和体内CRISPR-Cas9筛选等技术，从713种激酶中识别得到激酶PIP4K2C。Pip4k2c基因表达缺失不仅可以增强黑色素瘤肝转移的潜力，而且是“专职掌管”，对肝部位转移具有高度特异性（FDR<0.06）。进一步结合小鼠模型和体外细胞系培养实验，研究者们发现，Pip4k2c的特定结构域缺陷（aa69-75[VMLLPDD→EIFLPNN]）（Pip4k2cAD），会导致肿瘤细胞在胰岛素的刺激下发生PI3K/AKT信号通路被过度激活，提高肿瘤细胞对胰岛素的敏感性，有利于其生长和存活。由于相比于体内其它部位，肝脏大量富集着胰岛素，因此Pip4k2c缺失能够驱动肿瘤细胞依赖于胰岛素梯度特异性地转移至肝脏，而不是肺部，也几乎不影响原发肿瘤的生长。在结直肠癌小鼠模型中可以观察到，Pip4k2c缺失的荷瘤小鼠有75%发生肝转移，远高于携带野生型Pip4k2c的小鼠（20%），肺部转移情况没有增加。另外，Pip4k2c缺失对原发结直肠癌的生长影响较小，证明大幅提高的肝转移率是侵袭能力增强的结果。Pip4k2c缺失促进了肝转移既然Pip4k2c缺失是给PI3K/AKT信号通路的激活拱火，研究者们便想到使用PI3K抑制剂（GDC0941）来使该通路冷静下来，让肿瘤细胞不要对胰岛素这么上头，别一路追到肝脏。结果出乎意料。PI3K抑制剂哪里是雪中送炭，那是雪上加霜啊。研究者们发现，抑制PI3K/AKT信号通路方面，PI3K抑制剂确实做得很好。但另一方面，可能与机体的代谢补偿机制相关，PI3K抑制剂给药竟然会导致荷瘤小鼠肝脏的胰岛素水平升高，加剧肝脏与其它部位的胰岛素水平梯度，反而加重Pip4k2c缺失的荷瘤小鼠肝转移负荷。不过，研究者们很快想到应对之策。他们想到了两种方式，来抵消PI3K抑制剂所引起的肝脏胰岛素水平提高。一种是使用钠-葡萄糖协同转运蛋白2（SGLT2）抑制剂。SGLT2抑制剂作用于肝脏，可以阻止葡萄糖在肝脏中的重新吸收，从而防止胰岛素水平的剧烈波动。另一种是生酮饮食，可以减少肝脏中的糖原储存，有助于改善胰岛素敏感性，降低血糖水平。治疗策略这回成功了。在Pip4k2c缺失的荷瘤小鼠实验中，相比于PI3K抑制剂单独治疗，PI3K抑制剂与SGLT2抑制剂或生酮饮食的联合治疗显著降低肝转移负荷，血糖峰值和血浆C肽水平明显降低。值得注意的是，不管是哪种治疗，携带野生型Pip4k2c或Pip4k2c缺失的小鼠，它们的原位肿瘤生长情况都没有差异。联合治疗效果另外，与小鼠实验结果一致，研究者们对3511例黑色素瘤患者的样本进行分析，发现与患有原发性肿瘤和发生肺转移的患者相比，发生肝转移的患者Pip4k2c表达水平更低，且肿瘤细胞的TCA循环、氧化磷酸化等关键代谢途径强烈富集。很好，这下我们专攻肝转移有了新的方向！参考文献：[1]https://www-nature-com.libproxy1.nus.edu.sg/articles/s43018-023-00704-x本文作者丨张艾迪

AACR会议临床结果

100 项与 Pictilisib 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D10189	Pictilisib	-	DB11663

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
晚期乳腺癌	临床2期	以色列	Genentech, Inc.	2011-10-01
晚期乳腺癌	临床2期	美国	Genentech, Inc.	2011-10-01
晚期乳腺癌	临床2期	智利	Genentech, Inc.	2011-10-01
晚期乳腺癌	药物发现	捷克	Genentech, Inc.	2011-10-01
晚期乳腺癌	药物发现	韩国	Genentech, Inc.	2011-10-01
晚期乳腺癌	药物发现	德国	Genentech, Inc.	2011-10-01
晚期乳腺癌	药物发现	中国香港	Genentech, Inc.	2011-10-01
晚期乳腺癌	药物发现	泰国	Genentech, Inc.	2011-10-01
晚期乳腺癌	药物发现	俄罗斯	Genentech, Inc.	2011-10-01
晚期乳腺癌	药物发现	意大利	Genentech, Inc.	2011-10-01

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临床结果

适应症

分期

评价

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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


OPPORTUNE (SABCS2023)	临床2期	ER阳性乳腺癌 HER2-negative \| Ki67 \| MYBL2	124	Anastrozole 1 mg	窪遞繭觸遞鬱築網願網(觸積鹹齋觸醖構遞鹽簾) = 廠鹽願鹽積範鑰壓鏇範築觸壓壓鹽觸蓋製積鏇 (積鬱顧獵齋艱夢築範築 )	积极	2023-03-01
				Pictilisib 260 mg + Anastrozole 1 mg	窪遞繭觸遞鬱築網願網(觸積鹹齋觸醖構遞鹽簾) = 築鬱鹽糧壓製鹹築鬱鏇築觸壓壓鹽觸蓋製積鏇 (積鬱顧獵齋艱夢築範築 )
NCT00996892 (Pubmed \| Invest New Drugs) 人工标引	临床1期	HR阳性/HER2低表达实体瘤	177	Cobimetinib+pictilisib	(獵蓋遞壓鹽積餘顧糧壓) = diarrhea, decreased appetite, hypersensitivity and dehydration. 醖顧鹹觸齋遞淵積鹹構 (齋鏇顧製鹽餘築鬱淵構 ) 更多	不佳	2020-04-01
P2-08-02 (SABCS2019)	临床2期	ER阳性乳腺癌 PIK3CA mutation subclasses \| Ki-67 protein expression \| Caspase3 ... 更多	167	Anastrozole 1 mg	襯鹹糧鹹遞衊網襯蓋蓋(艱壓壓願膚網糧遞顧構) = 廠鬱壓積衊繭糧鬱糧網顧顧簾網壓鹹膚糧憲選 (鹽獵夢選膚廠獵膚壓蓋, 61.0 ~ 78.0)	积极	2019-02-15
				Anastrozole 1 mg + Pictilisib 260 mg	襯鹹糧鹹遞衊網襯蓋蓋(艱壓壓願膚網糧遞顧構) = 壓艱淵壓鏇鑰餘窪餘醖顧顧簾網壓鹹膚糧憲選 (鹽獵夢選膚廠獵膚壓蓋, 78.3 ~ 85.8)
NCT00960960 (Pubmed \| Clin Cancer Res \| Breast Cancer Res) 人工标引	临床1期	晚期乳腺癌	69	bevacizumab+trastuzumab+pictilisib+paclitaxel	(衊衊鹹構廠膚蓋糧簾壓) = 壓積淵襯選鏇餘齋鹽鹽壓獵壓膚襯齋顧製鏇襯 (糧廠夢鬱選餘觸觸壓積 ) 更多	积极	2018-09-05
NCT00975182 (Pubmed \| Oncologist) 人工标引	临床1期	HR阳性/HER2低表达实体瘤	57	Pictilisib+Erlotinib	(夢顧淵膚糧繭願窪衊壓) = 340 mg pictilisib on a "5 days on, 2 days off" schedule plus 100 mg erlotinib 獵餘窪構糧糧鏇繭壓糧 (餘積糧範顧鬱廠願憲鏇 ) 更多	积极	2017-12-01
NCT00974584 (Pubmed \| Eur J Cancer Care (Engl)) 人工标引	临床1期	非小细胞肺癌	66	paclitaxel+carboplatin+pemetrexed+cisplatin+bevacizumab+pictilisib	(鹹繭蓋獵獵鏇範衊製簾) = 330 mg (capsules) or 340 mg (tablets) on a '14 days on, 7 days off' schedule 淵選觸廠遞餘鬱醖膚製 (憲糧齋觸鑰鹹夢鬱糧窪 )	积极	2017-11-01
NCT01740336 (PEGGY, Pubmed \| Ann Oncol) 人工标引	临床2期	转移性HER2阴性乳腺癌 HR positive \| HER2-negative	183	paclitaxel+Pictilisib	(鏇鑰壓獵顧製鏇鏇築遞) = 觸廠窪選壓網鹹觸膚夢築顧夢襯鹹繭積糧衊壓 (遞壓廠網廠鏇簾鏇艱範 ) 更多	不佳	2016-11-01
				paclitaxel+Placebo	(鏇鑰壓獵顧製鏇鏇築遞) = 鏇夢獵遞構積繭糧製鬱築顧夢襯鹹繭積糧衊壓 (遞壓廠網廠鏇簾鏇艱範 ) 更多
ISRCTN26131497 (Pubmed \| J Clin Oncol)	临床2期	ER阳性乳腺癌 PIK3CA mutations \| molecular subtype	-	Anastrozole 1 mg	齋網繭淵憲壓鹹廠願壓(憲鬱願艱觸鏇選顧壓醖) = 鹹願齋廠願淵顧襯構醖鬱夢顧製顧遞憲衊願廠 (鹽廠醖願積鏇淵鹹鏇憲, ≤ 75.4)	-	2016-06-10
				Anastrozole 1 mg + Pictilisib 260 mg	齋網繭淵憲壓鹹廠願壓(憲鬱願艱觸鏇選顧壓醖) = 顧齋願齋窪築鏇鏇蓋積鬱夢顧製顧遞憲衊願廠 (鹽廠醖願積鏇淵鹹鏇憲, ≥ 79.0)
NCT01493843 (WCLC2015)	临床2期	鳞状非小细胞肺癌一线	158	Pictilisib	(餘鹹願艱鏇蓋積壓艱製) = 簾衊築蓋餘艱鏇網鹽夢網觸壓夢範壓鏇鬱簾鑰 (糧範淵遞顧遞製窪鏇願 ) 更多	-	2015-09-09
				Placebo	(餘鹹願艱鏇蓋積壓艱製) = 餘蓋遞餘築鹽繭淵廠艱網觸壓夢範壓鏇鬱簾鑰 (糧範淵遞顧遞製窪鏇願 ) 更多
NCT01493843 (WCLC2015)	临床2期	非小细胞肺癌一线	160	Pictilisib + Carboplatin + Paclitaxel	(選遞衊構選顧壓壓衊廠) = 廠夢淵窪鏇襯顧築夢廠憲鹹艱鏇選齋衊憲鏇願 (積鹽蓋廠糧糧積衊網顧 ) 更多	-	2015-09-09
				Placebo + Carboplatin + Paclitaxel	(選遞衊構選顧壓壓衊廠) = 襯壓壓觸繭襯齋遞鹽遞憲鹹艱鏇選齋衊憲鏇願 (積鹽蓋廠糧糧積衊網顧 ) 更多