Phosphoinositide 3-kinases (PI3Ks) are a family of ubiquitously distributed lipid kinases that
control a wide variety of intracellular signaling pathways. Over the years, PI3K has emerged as an attractive
target for the development of novel pharmaceuticals to treat cancer and various other diseases.
In the last five years, four of the PI3K inhibitors viz. Idelalisib, Copanlisib, Duvelisib, and Alpelisib
were approved by the FDA for the treatment of different types of cancer and several other PI3K inhibitors
are currently under active clinical development. So far clinical candidates are non-selective kinase
inhibitors with various off-target liabilities due to cross-reactivities. Hence, there is a need for the discovery
of isoform-selective inhibitors with improved efficacy and fewer side-effects. The development
of isoform-selective inhibitors is essential to reveal the unique functions of each isoform and its corresponding
therapeutic potential. Although the clinical effect and relative benefit of pan and isoformselective
inhibition will ultimately be determined, with the development of drug resistance and the demand
for next-generation inhibitors, it will continue to be of great significance to understand the potential
mechanism of isoform-selectivity. Because of the important role of type I PI3K family members in
various pathophysiological processes, isoform-selective PI3K inhibitors may ultimately have considerable
efficacy in a wide range of human diseases. This review summarizes the progress of isoformselective
PI3K inhibitors in preclinical and early clinical studies for anticancer and other various diseases.
Keywords: PI3K, Isoform-selective, Cancer, Inflammation, Thrombosis, Cardiovascular.
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