Overexpressed or mutationally activated ErbB family tyrosine kinases, including EGFR and Her-2, upregulate anti-apoptotic and cell proliferation signaling pathways, causing aberrant cell proliferation. Targeted cancer therapies directed against these kinases have been approved for treating colorectal, lung, and breast cancer. Cancer cell lines harboring upregulated ErbB kinase signaling have shown great response to small-molecule, ATP-competitive inhibitors such as gefitinib and lapatinib. Particularly, irreversible inhibitors such as afatinib act by dual-function mechanisms which involve tight binding to the ATP binding pocket of the enzyme and irreversible alkylation of solvent-exposed cysteine residues with arylamide electrophiles. The prolonged target interaction results in greater potency in cell lines that are resistant to reversible inhibitors. Here, we introduce a series of novel kinase inhibitors by conjugating ATP-mimicking quinazoline scaffolds with platinum-based cysteine-binding electrophiles. Unlike organic electrophiles, the sterically and electronically versatile platinum(II) center can be tuned efficiently. Several of the target molecules showed promising enzyme binding properties in competition binding assays and high selectivity for the targeted kinase domain in a panel of 145 clinically relevant kinases (KinomeScan, DiscoverX, Fremont, CA). A combinatorial library featuring different metal-containing moieties and inhibitor structures (see, for example, compounds 1 and 2, Figure 1) was assembled and screened for antiproliferative activity in NCI-H1975 lung cancer cells (L858R and T790M mutations in the EGFR kinase domain) and SK-BR-3 breast cancer cells (Her-2 positive) to identify hits and establish structure activity relationships. Some platinum-containing inhibitors exhibited enhanced activity compared to the unplatinated counterparts. In model reactions, compounds 1 and 2 transfer the platinum moiety to a cysteine-containing model peptide to form five-membered S,N-chelates. The covalent interactions of these hybrid agents with the kinase proteins were also studied by proteolytic digestion in conjunction with mass spectrometry, and peptide sequencing analysis.

Targeting ErbB tyrosine kinases with platinum-functionalized small molecule inhibitors

253rd National Meeting (2017)

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