https://pubs.acs.org/doi/10.1021/acs.jmedchem.0c01550
Background:
Deregulation of ALK was originally discovered by the identification of a t(2;5) chromosomal translocation in anaplastic large cell non-Hodgkin’s lymphoma (ALCL). The nucleophosmin (NPM)-ALK fusion protein produced by this translocation results in constitutive activation of the ALK kinase. Accordingly, ALK has been pursued as an attractive therapeutic target for treatment of various blood and solid tumors containing an ALK fusion (ALK-positive tumors).
Main Text:
Prof. Wang Shaomeng reported the discovery of a class of potent small-molecule inhibitors of anaplastic lymphoma kinase (ALK) containing a fused indoloquinoline scaffold. The most promising compound CJ-2360 has an IC50 value of 2.2 nM against wild-type ALK and low-nanomolar potency against several clinically reported ALK mutants. This compound is capable of achieving complete tumor regression in the ALK-positive KARPAS-299 xenograft model with oral administration in mice. CJ-2360 represents a promising ALK inhibitor for advanced preclinical development.
Synthesis:
Reagents and conditions: (a) (i) NCS, DABCO, DCM, 0 °C, 2 h; (ii) trichloroacetic acid, DCM, RT, 2 h; (b) Ph2O, reflux, 1 h; (c) 4-morpholinopiperidine or 1-methylpiperazine, DIPEA, DMSO, 120–140 °C, 3 days.
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