ML167

ML167 is a highly selective inhibitor of Cdc2-like kinase 4 (Clk4) with IC50 value of 136nM [1].

The Clk family enzymes play their roles in gene splicing via phosphorylating the major component of the spliceosome, SR proteins. Small molecule probes that target Clk’s can be used to study the modulating functions of these kinases in gene splicing. ML167 is found as the first fully selective inhibitor of Clk4 but not other related kinases including Clk1, Clk2 and Clk3 and Dyrk1A/1B. It is 10-fold more potent against Clk4 over other kinases. The treatment of ML167 on Caco-2 cells proves that ML167 is highly cell-permeable. Besides that, ML167 is also found to be an ATP-competitive inhibitor [1].

References:
[1] Rosenthal A S, Tanega C, Shen M, et al. An inhibitor of the Cdc2-like kinase 4 (Clk4). 2011.

Epidermal growth factor receptor (EGFR) structure-based bioactive pharmacophore models for identifying next-generation inhibitors against clinically relevant EGFR mutations.[Pubmed:28303669]

Chem Biol Drug Des. 2017 Oct;90(4):629-636.

Present work elucidates identification of next generation inhibitors for clinically relevant mutations of epidermal growth factor receptor (EGFR) using structure-based bioactive pharmacophore modeling followed by virtual screening (VS) techniques. Three-dimensional (3D) pharmacophore models of EGFR and its different mutants were generated. This includes seven 3D pharmacophoric points with three different chemical features (descriptors), that is, one hydrogen bond donor, three hydrogen bond acceptors and three aromatic rings. Pharmacophore models were validated using decoy dataset, Receiver operating characteristic plot, and external dataset compounds. The robust, bioactive 3D e-pharmacophore models were then used for VS of four different small compound databases: FDA approved, investigational, anticancer, and bioactive compounds collections of Selleck Chemicals. CUDC101 a multitargeted kinase inhibitor showed highest binding free energy and 3D pharmacophore fit value than the well known EGFR inhibitors, Gefitinib and Erlotinib. Further, we obtained ML167 as the second best hit on VS from bioactive database showing high binding energy and pharmacophore fit value with respect to EGFR receptor and its mutants. Optimistically, presented drug discovery based on the computational study serves as a foundation in identifying and designing of more potent EGFR next-generation kinase inhibitors and warrants further experimental studies to fight against lung cancer.

ML167 is a highly selective Cdc2-like kinase 4 (Clk4) inhibitor with IC50 of 136 nM, >10-fold selectivity for closely related kinases Clk1, Clk2, Clk3 and Dyrk1A/1B.

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