Brigatinib: New-generation ALK inhibitor for nonsmall cell lung cancer

Lung cancer, specifically nonsmall cell lung cancer (NSCLC) is the leading cause of death around the world. First-line therapies for metastatic NSCLC such as crizotinib, a tyrosine kinase inhibitor (TKI), have developed resistance due to a rearrangement of the anaplastic lymphoma kinase (ALK) gene. Brigatinib, approved in May 2016, is an ALK inhibitor specifically indicated for ALK-positive metastatic NSCLC in patients who have progressed on or resistant to crizotinib therapy. In several clinical trials, brigatinib has exhibited significant improvement in progression-free survival in patients that have experienced resistance to crizotinib therapy. The optimal dose of brigatinib was found to be 180 mg once daily and demonstrated greater efficacy as compared to its 90 mg once daily dose. Brigatinib was also found to be well tolerated. Although more studies are needed, the current data from these studies indicate brigatinib may be the most favorable therapeutic approach to treat NSCLC ALK..... READ ARTICLE

Current Problems in Cancer
DOI:10.1016/j.currproblcancer.2019.03.005

Authors: Stewart Umbela, Shahinaz Ghacha, Revika Matuknauth, Stacey Gause, Shrijana Joshee, Rahul R. Deshmukh

Review PaperKirk SmithDecember 1, 2019Brigatinib, Crizotinib-resistance, NSCLC, ALK, TKI

Discovery of 2-aminopyridines bearing a pyridone moiety as potent ALK inhibitors to overcome the crizotinib-resistant mutants

Despite the initial benefit demonstrated in clinical setting with ALK inhibitors, the challenging resistant mutants (F1174L, L1196M and G1202R) invariably developed. In this work, a series of 2-aminopyridine derivatives were designed and synthesized by C-5 position incorporation of a 2-pyridone moiety and bioisosteric replacement of the C-3 position linkers. Optimization of the 2-aminopyridine derivatives led to the identification of hit 18d displaying a significant growth inhibition against a variety of ALK-addicted cancer cells. Especially in the case of ALK-positive Karpas-299 cell, 18d exhibited excellent anti-proliferative potency with an IC50 value of about 40 nM. Moreover, 18d demonstrated encouraging activities against wild-type ALK (19 nM), ROS1 (2.3 nM) as well as challenging crizotinib-resistant ALKL1196M and ALKG1202R mutants with IC50 values of 45 nM and 22 nM, respectively. Additionally flow cytometric analysis indicates that 18d inhibited Karpas-299 cell viability via G1 phase arrest. Taken together, this work provided a promising ALK inhibitor to circumvent the clinical crizotinib-resistant mutants. READ ARTICLE

European Journal of Medicinal Chemistry DOI:10.1016/j.ejmech.2019.111734

Authors: Wenteng Chen, Xiao Guo, Can Zhang, Di Ke, Guolin Zhang, Yongping Yu

Pre-ClinicalKirk SmithDecember 1, 2019ALK inhibitors, Crizotinib-resistance, Solvent-front mutation, PyridoneLinker