1. Academic Validation
  2. AC0010, an Irreversible EGFR Inhibitor Selectively Targeting Mutated EGFR and Overcoming T790M-Induced Resistance in Animal Models and Lung Cancer Patients

AC0010, an Irreversible EGFR Inhibitor Selectively Targeting Mutated EGFR and Overcoming T790M-Induced Resistance in Animal Models and Lung Cancer Patients

  • Mol Cancer Ther. 2016 Nov;15(11):2586-2597. doi: 10.1158/1535-7163.MCT-16-0281.
Xiao Xu 1 2 Long Mao 3 2 Wanhong Xu 3 Wei Tang 3 Xiaoying Zhang 3 Biao Xi 2 Rongda Xu 3 2 Xin Fang 3 Jia Liu 3 2 Ce Fang 2 Li Zhao 2 Xiaobo Wang 3 2 Ji Jiang 4 Pei Hu 4 Hongyun Zhao 5 Li Zhang 6
Affiliations

Affiliations

  • 1 ACEA Pharmaceutical Research, Hangzhou, Zhejiang, P.R. China. [email protected] [email protected].
  • 2 ACEA Biosciences Inc., San Diego, California.
  • 3 ACEA Pharmaceutical Research, Hangzhou, Zhejiang, P.R. China.
  • 4 Peking Union Medical College Hospital, Beijing, P.R. China.
  • 5 Cancer Center, Sun Yat-Sen University, Guangzhou, Guangdong, P.R. China.
  • 6 Cancer Center, Sun Yat-Sen University, Guangzhou, Guangdong, P.R. China. [email protected] [email protected].
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.

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