title: AC0010, an Irreversible EGFR Inhibitor Selectively Targeting Mutated EGFR and Overcoming T790M-Induced Resistance in Animal Models and Lung Cancer Patients.
abstract: AC0010 is a pyrrolopyrimidine-based irreversible EGFR inhibitor, structurally distinct from previously reported pyrimidine-based irreversible EGFR inhibitors, such as osimertinib and rociletinib. AC0010 selectively inhibits EGFR-active and T790M mutations with up to 298-fold increase in potency compared with wild-type EGFR. In a xenograft model, oral administration of AC0010 at a daily dose of 500 mg/kg resulted in complete remission of tumors with EGFR-active and T790M mutations for over 143 days with no weight loss. Three major metabolites of AC0010 were tested and showed no wild-type EGFR inhibition or off-target effects, such as inhibition of IGF-1R. AC0010 is safe in non-small cell lung cancer (NSCLC) patients at a dose range between 50 and 550 mg once per day, and no hyperglycemia or other severe adverse effects were detected, such as grade 3 QT prolongation. The objective responses were observed in NSCLC patients with EGFR T790M mutation. Mol Cancer Ther; 15(11); 2586-97. ©2016 AACR.
authors: ACEA Pharmaceutical Research, Hangzhou, Zhejiang, P.R. China. xxu@aceabio.com zhangli6@mail.sysu.edu.cn.|ACEA Biosciences Inc., San Diego, California.
authors: Xiao
authors: X
authors: Xu
authors: ACEA Pharmaceutical Research, Hangzhou, Zhejiang, P.R. China.|ACEA Biosciences Inc., San Diego, California.
authors: Long
authors: L
authors: Mao
authors: ACEA Pharmaceutical Research, Hangzhou, Zhejiang, P.R. China.
authors: Wanhong
authors: W
authors: Xu
authors: ACEA Pharmaceutical Research, Hangzhou, Zhejiang, P.R. China.
authors: Wei
authors: W
authors: Tang
authors: ACEA Pharmaceutical Research, Hangzhou, Zhejiang, P.R. China.
authors: Xiaoying
authors: X
authors: Zhang
authors: ACEA Biosciences Inc., San Diego, California.
authors: Biao
authors: B
authors: Xi
authors: ACEA Pharmaceutical Research, Hangzhou, Zhejiang, P.R. China.|ACEA Biosciences Inc., San Diego, California.
authors: Rongda
authors: R
authors: Xu
authors: ACEA Pharmaceutical Research, Hangzhou, Zhejiang, P.R. China.
authors: Xin
authors: X
authors: Fang
authors: ACEA Pharmaceutical Research, Hangzhou, Zhejiang, P.R. China.|ACEA Biosciences Inc., San Diego, California.
authors: Jia
authors: J
authors: Liu
authors: ACEA Biosciences Inc., San Diego, California.
authors: Ce
authors: C
authors: Fang
authors: ACEA Biosciences Inc., San Diego, California.
authors: Li
authors: L
authors: Zhao
authors: ACEA Pharmaceutical Research, Hangzhou, Zhejiang, P.R. China.|ACEA Biosciences Inc., San Diego, California.
authors: Xiaobo
authors: X
authors: Wang
authors: Peking Union Medical College Hospital, Beijing, P.R. China.
authors: Ji
authors: J
authors: Jiang
authors: Peking Union Medical College Hospital, Beijing, P.R. China.
authors: Pei
authors: P
authors: Hu
authors: Cancer Center, Sun Yat-Sen University, Guangzhou, Guangdong, P.R. China.
authors: Hongyun
authors: H
authors: Zhao
authors: Cancer Center, Sun Yat-Sen University, Guangzhou, Guangdong, P.R. China. xxu@aceabio.com zhangli6@mail.sysu.edu.cn.
authors: Li
authors: L
authors: Zhang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008875:Middle Aged; D008958:Models, Molecular; D008968:Molecular Conformation; D009154:Mutation; D009367:Neoplasm Staging; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D066246:ErbB Receptors