Data driven polypharmacological drug design for lung cancer: analyses for targeting ALK, MET, and EGFR

Abstract

Drug design of protein kinase inhibitors is now greatly enabled by thousands of publicly available X-ray structures, extensive ligand binding data, and optimized scaffolds coming off patent. The extensive data begin to enable design against a spectrum of targets (polypharmacology); however, the data also reveal heterogeneities of structure, subtleties of chemical interactions, and apparent inconsistencies between diverse data types. As a result, incorporation of all relevant data requires expert choices to combine computational and informatics methods, along with human insight. Here we consider polypharmacological targeting of protein kinases ALK, MET, and EGFR (and its drug resistant mutant T790M) in non small cell lung cancer as an example. Both EGFR and ALK represent sources of primary oncogenic lesions, while drug resistance arises from MET amplification and EGFR mutation. A drug which inhibits these targets will expand relevant patient populations and forestall drug resistance. Crizotinib co-targets ALK and MET. Analysis of the crystal structures reveals few shared interaction types, highlighting proton-arene and key CH–O hydrogen bonding interactions. These are not typically encoded into molecular mechanics force fields. Cheminformatics analyses of binding data show EGFR to be dissimilar to ALK and MET, but its structure shows how it may be co-targeted with the addition of a covalent trap. This suggests a strategy for the design of a focussed chemical library based on a pan-kinome scaffold. Tests of model compounds show these to be compatible with the goal of ALK, MET, and EGFR polypharmacology.Electronic supplementary materialThe online version of this article (doi:10.1186/s13321-017-0229-8) contains supplementary material, which is available to authorized users.

Secondary Resistant Mutations to Small Molecule Inhibitors in Cancer Cells

“…Crizotinib, mentioned above, was one of the first drug used to target NSCLCs characterized by ALK fusions [172]. Crizotinib interacts with ALK similarly to MET through the L1196 gatekeeper residue (L1158 in MET), as well as the G1202 and G1269 residues [173,174]. Other interacting residues are also conserved between MET and ALK but no corresponding tyrosine residue (Y1248 MET) interaction is found in ALK.…”

Benzimidazoles: From Antiproliferative to Multitargeted Anticancer Agents

“…Such inhibitors challenge the dominant paradigm in drug discovery which deemed to design and develop bioactive agent with maximum selectivity and specificity to individual drug target. Such compounds hold the hope for a new avenue of combating disease cases that could not be cured with one inhibitor acting on single target such as cancer [104,105].…”

A Novel Forming Method of Traditional Chinese Medicine Dispersible Tablets to Achieve Rapid Disintegration Based on the Powder Modification Principle

“…Different from the crystalline structures of chemical medicine 15 , Chinese herbal extracts usually present as a paste or amorphous powder. The extracts are not typical insoluble substances for mixing with a large number of polysaccharides and other hydrophilic ingredients 16 .…”