Dual-Specificity Inhibitors of Lipid and Protein Kinases
Cancer cells survive by co-opting intracellular growth pathways regulated through kinase signaling. Many kinases in these pathways are validated drug targets and kinase inhibitors are first-line treatment for several advanced cancers. The first generation of kinase inhibitors were intended to target single proteins. However, the highly conserved active sites of protein kinases prohibited the design of perfectly selective inhibitors. Unexpectedly, this specificity problem led to the development of clinically useful, multi-targeted kinase inhibitors. Clinically, multi-targeted inhibitors were found to have high efficacy and low toxicity. At a molecular level, this translated into simultaneous inhibition of critical nodes in a signaling network regulated by multiple inputs and levels of feedback.
Two kinase families, phosphoinositide-3-kinases (PI3Ks) and protein tyrosine kinases (PTKs), are activated by mutations and amplifications in a disproportionate number of human cancers. This suggests multi-targeted therapy inhibiting PI3Ks and PTKs may be extremely effective at blocking the signaling networks that are essential for cancer cell survival. The design of dual PI3K/PTK inhibitors is chemically challenging because PI3Ks and PTKs are members of significantly divergent kinase families. However, druggable similarities exist between these two families due to structural features essential for phosphoryl transfer with ATP as the phosphate donor.
We report the first drug-like small molecules that potently and selectively inhibit PTKs and PI3Ks. These agents were developed by exploiting structural similarities in kinase active sites. Through iterative medicinal chemistry, kinome profiling and x-ray crystallography, the chemical and structural features that control the in vitro selectivity and potency of these compounds were defined. A subset of these compounds potently, and sometimes selectively, inhibit the mammalian target of rapamycin (mTOR), a Ser/Thr kinase in the PI3K family, placing mTOR in kinase space at the intersection of PI3Ks and PTKs. Subsequent cell-based experiments demonstrated these compounds inhibit their molecular targets in cells, block cancer cell proliferation and angiogenesis, and maintain activity against cells harboring mutations rendering them resistant to singly-targeted agents.