产品号 #73152_C
PI3K/AKT通路抑制剂；抑制I类PI3k
总览
GDC-0941是磷脂酰肌醇-4,5-二磷酸3激酶（PI3K）的抑制剂。它通过在ATP结合口袋附近结合，抑制PI3K的I类催化亚基p110α、β、δ和γ，IC₅₀值分别为3、33、3和75 nM (Folkes等人；Berndt 等人)。对II、III、IV类PI3K亚型也有选择性，但有效性较低；例如，它对II类磷脂酰肌醇-4-磷酸3-激酶C2结构域β亚基（C2β）和 IV 类的哺乳动物雷帕霉素靶蛋白（mTOR）的抑制作用在高纳摩尔浓度范围内，而对其他大多数 PI3K 亚型的抑制作用则在微摩尔范围内（Folkes 等人）。
癌症研究
·在体外和小鼠异种移植模型中，抑制多种癌细胞系的增殖，如U87MG（胶质母细胞瘤）、PC3（前列腺）和MDA-MB-361（乳腺）细胞系（Folkes等人；雷诺等人；O 'Brien等人)。
·与MAP/ERK激酶（MEK）抑制剂GDC-0973联合使用时，可诱导细胞凋亡并抑制异种移植物肿瘤生长（Hoeflich等人）。
细胞类型
癌细胞及细胞系
种属
人，小鼠，非人灵长类，其它细胞系，大鼠
研究领域
癌症
CAS 编号
957054-30-7
化学式
C₂₃H₂₇N₇O₃S₂
纯度
≥98%
通路
PI3K/AKT
靶点
PI3K
Protocols and Documentation
Find supporting information and directions for use in the Product Information Sheet or explore additional protocols below.
Resources and Publications
Educational Materials (2)
Publications (6)
First-in-human phase I study of pictilisib (GDC-0941), a potent pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor, in patients with advanced solid tumors. Clinical cancer research : an official journal of the American Association for Cancer Research 2015
Abstract
PURPOSE: This first-in-human dose-escalation trial evaluated the safety, tolerability, maximal-tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics, pharmacodynamics, and preliminary clinical activity of pictilisib (GDC-0941), an oral, potent, and selective inhibitor of the class I phosphatidylinositol-3-kinases (PI3K). PATIENTS AND METHODS: Sixty patients with solid tumors received pictilisib at 14 dose levels from 15 to 450 mg once-daily, initially on days 1 to 21 every 28 days and later, using continuous dosing for selected dose levels. Pharmacodynamic studies incorporated (18)F-FDG-PET, and assessment of phosphorylated AKT and S6 ribosomal protein in platelet-rich plasma (PRP) and tumor tissue. RESULTS: Pictilisib was well tolerated. The most common toxicities were grade 1-2 nausea, rash, and fatigue, whereas the DLT was grade 3 maculopapular rash (450 mg, 2 of 3 patients; 330 mg, 1 of 7 patients). The pharmacokinetic profile was dose-proportional and supported once-daily dosing. Levels of phosphorylated serine-473 AKT were suppressed textgreater90% in PRP at 3 hours after dose at the MTD and in tumor at pictilisib doses associated with AUC textgreater20 htextperiodcenteredμmol/L. Significant increase in plasma insulin and glucose levels, and textgreater25% decrease in (18)F-FDG uptake by PET in 7 of 32 evaluable patients confirmed target modulation. A patient with V600E BRAF-mutant melanoma and another with platinum-refractory epithelial ovarian cancer exhibiting PTEN loss and PIK3CA amplification demonstrated partial response by RECIST and GCIG-CA125 criteria, respectively. CONCLUSION: Pictilisib was safely administered with a dose-proportional pharmacokinetic profile, on-target pharmacodynamic activity at dose levels ≥100 mg and signs of antitumor activity. The recommended phase II dose was continuous dosing at 330 mg once-daily.
Intermittent administration of MEK inhibitor GDC-0973 plus PI3K inhibitor GDC-0941 triggers robust apoptosis and tumor growth inhibition. Cancer research 2012
Abstract
Combinations of MAP/ERK kinase (MEK) and phosphoinositide 3-kinase (PI3K) inhibitors have shown promise in preclinical cancer models, leading to the initiation of clinical trials cotargeting these two key cancer signaling pathways. GDC-0973, a novel selective MEK inhibitor, and GDC-0941, a class I PI3K inhibitor, are in early stage clinical trials as both single agents and in combination. The discovery of these selective inhibitors has allowed investigation into the precise effects of combining inhibitors of two major signaling branches downstream of RAS. Here, we investigated multiple biomarkers in the mitogen-activated protein kinase (MAPK) and PI3K pathway to search for points of convergence that explain the increased apoptosis seen in combination. Using washout studies in vitro and alternate dosing schedules in mice, we showed that intermittent inhibition of the PI3K and MAPK pathway is sufficient for efficacy in BRAF and KRAS mutant cancer cells. The combination of GDC-0973 with the PI3K inhibitor GDC-0941 resulted in combination efficacy in vitro and in vivo via induction of biomarkers associated with apoptosis, including Bcl-2 family proapoptotic regulators. Therefore, these data suggest that continuous exposure of MEK and PI3K inhibitors in combination is not required for efficacy in preclinical cancer models and that sustained effects on downstream apoptosis biomarkers can be observed in response to intermittent dosing.
The p110 delta structure: mechanisms for selectivity and potency of new PI(3)K inhibitors. Nature chemical biology 2010
Abstract
Deregulation of the phosphoinositide-3-OH kinase (PI(3)K) pathway has been implicated in numerous pathologies including cancer, diabetes, thrombosis, rheumatoid arthritis and asthma. Recently, small-molecule and ATP-competitive PI(3)K inhibitors with a wide range of selectivities have entered clinical development. In order to understand the mechanisms underlying the isoform selectivity of these inhibitors, we developed a new expression strategy that enabled us to determine to our knowledge the first crystal structure of the catalytic subunit of the class IA PI(3)K p110 delta. Structures of this enzyme in complex with a broad panel of isoform- and pan-selective class I PI(3)K inhibitors reveal that selectivity toward p110 delta can be achieved by exploiting its conformational flexibility and the sequence diversity of active site residues that do not contact ATP. We have used these observations to rationalize and synthesize highly selective inhibitors for p110 delta with greatly improved potencies.
更多信息
| Species | Human, Mouse, Non-Human Primate, Other, Rat |
|---|---|
| Cas Number | 957054-30-7 |
| Chemical Formula | C₂₃H₂₇N₇O₃S₂ |
| Purity | ≥ 98% |
| Target | PI3K |
| Pathway | PI3K/AKT |
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