Anaplastic lymphoma kinase (ALK) is an orphan receptor tyrosine kinase (RTK), structurally belonging to the insulin receptor family. The identification of ALK fusion genes NPM-ALK and EML4-ALK in ALCL and NSCLC respectively, and clinical outcomes resulting from aberrant ALK signalling in different human cancers has confirmed the emergence of ALK as a novel and promising ‘personalized’ anticancer drug target. The development of small molecule ALK inhibitors has been accelerated and validated by the recent approval of crizotinib. Unfortunately, similar to other RTK inhibitors, resistance to crizotinib has been reported within a year of starting therapy. Different from the acquired resistance to EGFR inhibitors, the resistance to crizotinib was much more complex and driven by more than twenty secondary mutations, including the gate-keeper L1196M, and the C1156Y near the α-C-helix. In the course of our drug discovery program toward the discovery of novel ALK inhibitors, we took advantage of the 2,4-diarylaminopyrimidine (DAAP) scaffold that has long been recognized as a classical kinase inhibitor motif (TAE684) by introducing an amino acid side chain to the solvent interaction region to bring in additional H-bondings. Therefore, a series of new DAAP analogues (DAAPalogues) were developed and one compound SOMCL-12-81 was identified with high potency against both wild type ALK and L1196M mutations with IC50 values of 2.7 nM and 15.3 nM, respectively. In cellular assay, SOMCL-12-81 displayed an IC50 value of 3.0 nM against the proliferation of EML4-ALK dependent Karpass-299 cells. It was relatively selective (>10-fold) against a panel of in-house 20 RTKs. Dose-dependent tumor growth inhibition was observed in the BF3 rat xenograft model carrying the EML4-ALK fusion gene with daily administration of SOMCL-12-81. The high potency of SOMCL-12-81 both in vitro and in vivo allows it for further investigation.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B99.

Citation Format: Zilan Song, Jing Ai, Zhiqing Liu, Xia Peng, Yi Chen, Jian Ding, Meiyu Geng, Ao Zhang. Discovery of 2,4-diarylaminopyrimidine SOMCL-12-81 as a potent inhibitor targeting both wild and mutant ALK kinases. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B99.