氧代吡啶并[2,3-d]嘧啶类作为共价L858R/T790M突变体选择性表皮生长因子受体（EGFR）抑制剂
Oxopyrido[2,3-d]pyrimidines as Covalent L858R/T790M Mutant Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors.
作者信息
Wurz Ryan P, Pettus Liping H, Ashton Kate, Brown James, Chen Jian Jeffrey, Herberich Brad, Hong Fang-Tsao, Hu-Harrington Essa, Nguyen Tom, St Jean David J, Tadesse Seifu, Bauer David, Kubryk Michele, Zhan Jinghui, Cooke Keegan, Mitchell Petia, Andrews Kristin L, Hsieh Faye, Hickman Dean, Kalyanaraman Nataraj, Wu Tian, Reid Darren L, Lobenhofer Edward K, Andrews Dina A, Everds Nancy, Guzman Roberto, Parsons Andrew T, Hedley Simon J, Tedrow Jason, Thiel Oliver R, Potter Matthew, Radinsky Robert, Beltran Pedro J, Tasker Andrew S
机构信息
Medicinal Chemistry, Oncology Research, Molecular Structure, Pharmacokinetics and Drug Metabolism, Oral Delivery - Product and Process Development, Discovery Toxicology, Pathology, Chemical Process R&D, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
Medicinal Chemistry, Chemical Process R&D, Analytical R&D, Amgen Inc. , 360 Binney Avenue, Cambridge, Massachusetts 02142-1011, United States.
出版信息
ACS Med Chem Lett. 2015 Jul 27;6(9):987-92. doi: 10.1021/acsmedchemlett.5b00193. eCollection 2015 Sep 10.
In nonsmall cell lung cancer (NSCLC), the threonine(790)-methionine(790) (T790M) point mutation of EGFR kinase is one of the leading causes of acquired resistance to the first generation tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib. Herein, we describe the optimization of a series of 7-oxopyrido[2,3-d]pyrimidinyl-derived irreversible inhibitors of EGFR kinase. This led to the discovery of compound 24 which potently inhibits gefitinib-resistant EGFR(L858R,T790M) with 100-fold selectivity over wild-type EGFR. Compound 24 displays strong antiproliferative activity against the H1975 nonsmall cell lung cancer cell line, the first line mutant HCC827 cell line, and promising antitumor activity in an EGFR(L858R,T790M) driven H1975 xenograft model sparing the side effects associated with the inhibition of wild-type EGFR.
在非小细胞肺癌（NSCLC）中，表皮生长因子受体（EGFR）激酶的苏氨酸（790）-甲硫氨酸（790）（T790M）点突变是导致对第一代酪氨酸激酶抑制剂（TKIs），如吉非替尼和厄洛替尼产生获得性耐药的主要原因之一。在此，我们描述了一系列7-氧代吡啶并[2,3-d]嘧啶基衍生的EGFR激酶不可逆抑制剂的优化过程。这导致了化合物24的发现，该化合物能有效抑制吉非替尼耐药的EGFR（L858R，T790M），对野生型EGFR的选择性是其100倍。化合物24对H1975非小细胞肺癌细胞系、一线突变HCC827细胞系显示出强大的抗增殖活性，并且在EGFR（L858R，T790M）驱动的H1975异种移植模型中显示出有前景的抗肿瘤活性，同时避免了与抑制野生型EGFR相关的副作用。
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