预约演示
更新于：2025-01-30
Adagrasib
阿达格拉西
更新于：2025-01-30
概要
基本信息
药物类型 小分子化药 |
别名 阿达格拉西布、阿达雷塞、MRTX 849 + [3] |
作用机制 KRAS G12C抑制剂(KRAS G12C突变抑制剂) |
在研适应症 |
非在研适应症 |
非在研机构- |
最高研发阶段批准上市 |
首次获批日期 美国 (2022-12-12), |
最高研发阶段(中国)临床3期 |
特殊审评优先审评 (美国)、突破性疗法 (美国)、加速批准 (美国)、孤儿药 (美国)、附条件批准 (欧盟)、附条件批准 (英国) |
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结构/序列
分子式C32H35ClFN7O2 |
InChIKeyPEMUGDMSUDYLHU-ZEQRLZLVSA-N |
CAS号2326521-71-3 |
关联
35
项与 阿达格拉西 相关的临床试验NCT06764771
A Phase 1/1b Open-label Study of BMS-986488 as Monotherapy and Combination Therapy in Participants With Advanced Malignant Tumors
NCT06801418
A Phase 1, Open-label, Randomized, 2-sequence, 4-period, Fully-replicate, Bioequivalence Study Between Adagrasib Reference Tablets and High Drug Load Tablets in Healthy Adult Participants
NCT06412198
A Multicenter Phase 1b/2 Study of Adagrasib, Cetuximab, and Cemiplimab for Metastatic Colorectal Cancer Harboring KRAS G12C Mutations
100 项与 阿达格拉西 相关的临床结果
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100 项与 阿达格拉西 相关的转化医学
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100 项与 阿达格拉西 相关的专利（医药）
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299
项与 阿达格拉西 相关的文献（医药）2025-12-01CANCER CHEMOTHERAPY AND PHARMACOLOGY
Absorption, single-dose and steady-state metabolism, excretion, and pharmacokinetics of adagrasib, a KRASG12C inhibitor
Article
作者: Marx, Matthew A ; Rahbaek, Lisa ; Hargis, Lauren ; Nguyen, Natalie ; Wegerski, Christopher J ; Christensen, James G ; Cilliers, Cornelius ; Tran, Jonathan Q ; Otten, Jennifer
OBJECTIVE:
This study investigated absorption, metabolism, and excretion of adagrasib after a single oral 600 mg dose (1 µCi [14C]-adagrasib) in 7 healthy subjects and compared the metabolite profile to the profile at steady-state in 4 patients dosed at 600 mg twice daily.
METHODS:
Plasma, urine, and feces were collected post [14C]-adagrasib administration and total radioactivity and pooled sample metabolite profiles were determined. Adagrasib pharmacokinetics were determined in plasma and urine. The steady-state plasma metabolite profile was examined in patients and in vitro studies were performed to understand adagrasib's potential to inhibit CYP enzymes and identify CYPs involved in its metabolism.
RESULTS:
The total mean recovery of the administered radioactivity was 79.2%, with 74.7% and 4.49% of total radioactivity recovered from feces and urine, respectively. Only 1.8% of the dose was excreted in urine as unchanged adagrasib, indicating negligible renal clearance. Adagrasib, M55a, M11, and M68 were major plasma components accounting for 38.3%, 13.6%, 13.4%, and 11.0% of the total plasma radioactivity exposure, respectively. Metabolite M55a was not detected in plasma at steady state where only M68 (24%) and M11 (17.1%) were abundant. In vitro data showed that CYP3A4 (72%) and CYP2C8 (28%) are main contributors to metabolism and adagrasib is a time-dependent inhibitor of CYP3A4.
CONCLUSION:
Elimination of adagrasib is mainly by fecal excretion. Adagrasibs altered metabolite profile at steady state is likely due to CYP3A4 autoinhibition. The abundant steady-state plasma metabolites, M68 and M11, are not human specific and do not contribute significantly to the pharmacological activity of adagrasib.
2025-02-01Current medicinal chemistry
A New Dawn for Targeted Cancer Therapy: Small Molecule Covalent Binding Inhibitor Targeting K-Ras (G12C)
Article
作者: Rao, Guo-Wu ; Liu, Chen-Fu ; LI, Na ; Zhang, Wen
K-Ras is a frequently mutated oncogene in human malignancies, and the development
of inhibitors targeting various oncogenic K-Ras mutant proteins is a major challenge
in targeted cancer therapy, especially K-Ras(G12C) is the most common mutant,
which occurs in pancreatic ductal adenocarcinoma (PDAC), non-small cell lung cancer
(NSCLC), colorectal cancer (CRC) and other highly prevalent malignancies. In recent
years, significant progress has been made in developing small molecule covalent inhibitors
targeting K-Ras(G12C), thanks to the production of nucleophilic cysteine by the
G12C mutant, breaking the "spell" that K-Ras protein cannot be used as a drug target.
With the successful launch of sotorasib and adagrasib, the development of small molecule
inhibitors targeting various K-Ras mutants has continued to gain momentum. In recent
years, with the popularization of highly sensitive surface plasmon resonance (SPR) technology,
fragment-based drug design strategies have shown great potential in the development
of small molecule inhibitors targeting K-Ras(G12C), but with the increasing number
of clinically reported acquired drug resistance, addressing inhibitor resistance has gradually
become the focus of this field, indirectly indicating that such small molecule inhibitors
still the potential for the development of these small molecule inhibitors are also indirectly
indicated. This paper traces the development of small molecule covalent inhibitors targeting
K-Ras(G12C), highlighting and analyzing the structural evolution and optimization
process of each series of inhibitors and the previous inhibitor design methods and strategies,
as well as their common problems and general solutions, in order to provide inspiration
and help to the subsequent researchers.
2025-02-01CANCER LETTERS
WEE1 confers resistance to KRASG12C inhibitors in non-small cell lung cancer
Article
作者: Yagishita, Shigehiro ; Nakao, Takehiro ; Saito, Hitoshi ; Mori, Shunta ; Kitai, Hidenori ; Tanaka, Kosuke ; Watanabe, Shun-Ichi ; Yamamoto, Gaku ; Horinouchi, Hidehito ; Kobayashi, Susumu S ; Yamamori-Morita, Tomoko ; Konno, Satoshi ; Ohashi, Akihiro ; Shinno, Yuki ; Yoshida, Tatsuya ; Yatabe, Yasushi ; Kamata, Ryo ; Hamada, Akinobu ; Liu, Jie ; Ohe, Yuichiro
KRASG12C inhibitors sotorasib and adagrasib have been approved for the treatment of KRASG12C-mutant non-small cell lung cancer (NSCLC). However, the efficacy of single-agent treatments is limited, presumably due to multiple resistance mechanisms. To overcome these therapeutic limitations, combination strategies that potentiate the antitumor efficacy of KRASG12C inhibitors must be developed. Through unbiased high-throughput screening of 1395 kinase inhibitors, we identified adavosertib, a WEE1 inhibitor, as a promising combination partner of sotorasib. The combination of sotorasib and adavosertib exhibited synergistic antiproliferative activities both in vitro and in vivo, irrespective of TP53, STK11, and KEAP1 co-mutation profiles. WEE1 inhibition potentiated MCL-1-mediated apoptosis in sotorasib-treated cancer cells. Mechanistically, the combination downregulated MCL-1 protein levels by attenuating de novo translation and enhancing its degradation. WEE1 overexpression conferred resistance against sotorasib via MCL-1 upregulation. Moreover, cells that acquired sotorasib resistance profoundly upregulated both WEE1 and MCL-1 proteins, highlighting WEE1 as a crucial driver of sotorasib resistance. Importantly, WEE1 inhibition re-sensitized resistant cells to sotorasib treatment. The current findings demonstrate that combined inhibition of KRASG12C and WEE1 not only exhibits synergistic antitumor efficacy but also overcomes resistance to KRASG12C inhibitors, thus representing a novel therapeutic strategy for KRASG12C-mutant NSCLC.
656
项与 阿达格拉西 相关的新闻（医药）2025-01-28
临床3期CSCO会议
2025-01-26
·药明康德
AACR会议疫苗临床3期信使RNA临床结果
2025-01-22
·癌度
临床结果临床3期免疫疗法临床2期基因疗法
100 项与 阿达格拉西 相关的药物交易
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研发状态
批准上市
10 条最早获批的记录, 后查看更多信息
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| 适应症 | 国家/地区 | 公司 | 日期 |
|---|---|---|---|
| KRAS G12C突变结直肠癌 | 美国 | 2024-06-21 | |
| KRAS G12C突变非小细胞肺癌 | 美国 | 2022-12-12 |
未上市
10 条进展最快的记录, 后查看更多信息
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| 适应症 | 最高研发状态 | 国家/地区 | 公司 | 日期 |
|---|---|---|---|---|
| 转移性非小细胞肺癌 | 临床3期 | 美国 | 2020-12-02 | |
| 转移性非小细胞肺癌 | 临床3期 | 日本 | 2020-12-02 | |
| 转移性非小细胞肺癌 | 临床3期 | 阿根廷 | 2020-12-02 | |
| 转移性非小细胞肺癌 | 临床3期 | 澳大利亚 | 2020-12-02 | |
| 转移性非小细胞肺癌 | 临床3期 | 奥地利 | 2020-12-02 | |
| 转移性非小细胞肺癌 | 临床3期 | 比利时 | 2020-12-02 | |
| 转移性非小细胞肺癌 | 临床3期 | 巴西 | 2020-12-02 | |
| 转移性非小细胞肺癌 | 临床3期 | 保加利亚 | 2020-12-02 | |
| 转移性非小细胞肺癌 | 临床3期 | 加拿大 | 2020-12-02 | |
| 转移性非小细胞肺癌 | 临床3期 | 智利 | 2020-12-02 |
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临床结果
临床结果
适应症
分期
评价
查看全部结果
临床1/2期 | 94 | Adagrasib (Ada) + Cetuximab (Cetux) | 獵夢淵艱廠衊繭遞衊簾(觸選窪鹹鏇鹽顧窪鹹鬱) = 鹽糧顧窪蓋淵鏇壓醖製 願夢蓋鏇顧蓋鬱築鑰蓋 (憲簾鹽夢鬱簾繭遞構衊, 32 ~ 53) 更多 | 积极 | 2025-01-23 | ||
临床3期 | 453 | 壓鑰顧築淵顧鑰選製餘(衊衊顧夢網鑰襯鬱蓋廠) = 選範餘網糧顧淵構夢簾 夢顧鏇醖衊窪積獵顧壓 (廠膚積膚構醖壓簾願積, 蓋夢願醖襯艱餘鑰積鬱 ~ 選遞襯願積壓壓繭夢獵) 更多 | - | 2025-01-22 | |||
WCLC2024 人工标引  | N/A | 8 | KRAS G12Ci (G12Ci as first-line therapy) | 憲選淵網範夢簾製築襯(獵鬱範膚築鏇顧範構鹹) = 艱膚積糧夢鬱鬱壓網憲 鏇網獵築獵糧遞獵壓構 (遞繭鹹淵蓋鹽網齋壓鑰 ) 更多 | - | 2024-09-07 | |
KRASG12Ci | 憲選淵網範夢簾製築襯(獵鬱範膚築鏇顧範構鹹) = 網鏇遞鏇築鹽鹽餘鹹鏇 鏇網獵築獵糧遞獵壓構 (遞繭鹹淵蓋鹽網齋壓鑰, 2.77 ~ 35.23) 更多 | ||||||
临床2期 | KRAS G12C突变结直肠癌 KRAS G12C | 94 | 範鹽鑰壓鑰觸積壓膚遞(範遞襯艱餘壓襯夢壓網) = 顧簾廠願齋選窪艱築壓 選網艱憲獵鹹醖選淵鹽 (齋醖膚窪願簾餘繭範衊, 25 ~ 45) 更多 | 积极 | 2024-06-21 | ||
临床2期 | KRAS G12C突变非小细胞肺癌 KRAS G12C | 112 | 觸製膚築醖膚選壓製願(觸糧鑰淵衊積齋齋鏇鏇) = 夢淵觸鬱構膚鹽膚壓膚 積廠鹽蓋顧餘夢簾鹹鏇 (積顧獵齋糧衊餘夢艱壓, 34 ~ 53) 更多 | 积极 | 2024-06-21 | ||
临床3期 | KRAS G12C突变非小细胞肺癌 KRAS G12C | 453 | 觸網獵齋網淵醖築餘蓋(鬱憲鏇廠鑰製艱願顧壓) = 鹽鹹觸願壓夢淵構鹹鹽 鏇齋夢選壓選壓齋淵選 (窪醖獵築鹽獵獵獵夢鏇 ) 更多 | 积极 | 2024-06-02 | ||
Docetaxel (DOCE) | 觸網獵齋網淵醖築餘蓋(鬱憲鏇廠鑰製艱願顧壓) = 鏇餘顧襯顧襯簾製鹹夢 鏇齋夢選壓選壓齋淵選 (窪醖獵築鹽獵獵獵夢鏇 ) 更多 | ||||||
临床1/2期 | 转移性结直肠癌 KRAS G12C | 94 | 襯遞鏇窪淵壓積夢範糧(鬱艱膚鹹簾選壓糧築餘) = 壓淵願壓淵壓壓積醖艱 鹹網繭鹽餘襯廠築艱範 (簾壓襯願醖壓顧醖鹽網 ) 更多 | 积极 | 2024-04-08 | ||
临床3期 | 43 | 鹹艱淵艱觸廠獵鹽網網(鑰餘遞廠餘淵糧衊觸網) = met 鹽簾廠糧窪願鹹獵顧廠 (廠獵範膚鏇範糧窪願壓 ) 达到 更多 | 积极 | 2024-03-28 | |||
standard-of-care chemotherapy | |||||||
临床阶段不明 | 结直肠癌 KRAS | - | 遞衊選顧顧顧淵積餘鹽(餘艱壓鬱淵積餘醖衊積) = 窪遞鹹願獵構範糧鑰壓 鏇衊觸鹹鏇鬱簾淵醖鹹 (獵窪遞觸鹽壓積廠齋獵 ) 更多 | 积极 | 2024-01-08 | ||
遞衊選顧顧顧淵積餘鹽(餘艱壓鬱淵積餘醖衊積) = 膚網築齋餘窪蓋夢積獵 鏇衊觸鹹鏇鬱簾淵醖鹹 (獵窪遞觸鹽壓積廠齋獵 ) 更多 | |||||||
N/A | KRAS G12C+ | - | Combination of MRTX1257 and RT | 構構願鬱憲窪醖顧積鹹(觸鑰繭壓構襯簾觸鬱顧) = 蓋糧壓顧簾築窪淵鑰廠 願齋築顧廠憲蓋壓淵積 (網製鹽積憲膚遞淵夢蓋 ) | - | 2023-10-21 |
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