These are small molecule dual kinase inhibitors that can be used for therapeutic agents for cancer. They act on two kinases from the MAP kinase and PI3K signal transduction pathways that regulate cell survival and proliferation, and are both implicated in tumor growth, progression, and metastasis. Targeted monotherapies that act on specific kinases found in these pathways often lack efficacy and tumors quickly develop resistance. Since the Ras/Raf/MEK/ERK and PI3K/AKT/mTOR pathways are two of the most commonly deregulated in cancer, effective agents could potentially have a huge market, especially for tumors harboring Ras oncogenic mutations, which have been notoriously difficult to treat.
Potent Single Molecule MEK and PI3K Dual Pathway Inhibitors
Researchers in the Radiology Department at the University of Michigan developed dual MEK/PI3K kinase inhibitors with potent cellular activity. To create this new compound, the researchers combined individual PI3K and MEK inhibitors into a single molecule using a linker that did not affect the individual binding affinity. The resulting compound has an IC50 = 370 nM against PI3K and IC50 = 501 nM against MEK. Additional analogs are being evaluated for improvement in potency and in vivo stability. Combining inhibitors of several signaling pathways such as Ras/Raf/MEK/ERK and PI3K/AKT/mTOR pathways has been recognized as a potentially beneficial strategy to improve efficacy of monotherapy approaches and prevent or delay emergence of tumor resistance. However, developing two investigational compounds is daunting as complexities arise from trying to match different administration schedules and differing pharmacokinetics, as well as managing overlapping side effects. For this reason, having a single molecule that simultaneously inhibits both pathways is advantageous for drug development.
Applications • New therapeutic compound for treatment of cancer
Advantages • Single molecule dual pathway inhibitor • Easier development than combination therapy • Potential to improve efficacy and prevent or delay tumor resistance • Potential to treat highly recalcitrant tumors