12 June 2019 - - US-based Deciphera Pharmaceuticals, Inc. (NASDAQ: DCPH) has added a new candidate to its pipeline, DCC-3116, a potential first-in-class small molecule designed to inhibit cancer autophagy, a key tumor survival mechanism, the company said.
DCC-3116, discovered using the company's novel switch control inhibitor platform, is designed to inhibit autophagy by inhibiting the ULK kinase.
Autophagy is a cellular pathway that has been shown to be upregulated in mutant RAS cancers and that also mediates resistance to inhibitors of the RAS signaling pathway.
Subject to favorable investigational new drug -enabling studies and filing and activation of an IND, Deciphera intends to develop DCC-3116 for the potential treatment of mutant RAS cancers in combination with inhibitors of downstream effector targets including RAF, MEK, or ERK inhibitors as well as with direct inhibitors of mutant RAS.
Based on pre-clinical studies, DCC-3116 selectively inhibits ULK kinase, believed to be the initiating factor that activates autophagy.
Autophagy is a cell survival pathway in which cells respond to stress by recycling their own components and/or clearing damaged organelles and proteins from the cell.
Mutant RAS cancers, including KRAS, NRAS, and HRAS cancers, are reported to have high basal levels of autophagy, which they use to maintain nutrient supply, regulate cancer cell metabolism, and mitochondria surveillance.
In multiple in vitro and in vivo models of mutant RAS cancers, autophagy inhibition combined with inhibition of MAPK signaling using MEK inhibitors or ERK inhibitors has demonstrated synergistic anti-tumor effects.
When used in pre-clinical in vitro and in vivo studies in combination with inhibitors of the MAPK pathway, DCC-3116 synergized with these inhibitors to inhibit mutant RAS cancer growth.
Cellular studies in mutant RAS cancers have demonstrated that MAPK pathway inhibitors further activate autophagy as a compensatory survival mechanism. Such activation of autophagy is seen with RAF, MEK, and ERK inhibitors as well as with direct inhibitors of mutant KRAS G12C.
As an inhibitor of ULK, DCC-3116 is designed to address mutant RAS cancers by inhibiting the basal and compensatory autophagy that mutant RAS cancer cells use for their survival.
Deciphera is currently conducting IND-enabling studies for DCC-3116 and, pending favorable results, expects to file an IND in mid-2020.
Deciphera Pharmaceuticals is a clinical-stage biopharmaceutical company focused on improving the lives of cancer patients by tackling key mechanisms of drug resistance that limit the rate and/or durability of response to existing cancer therapies.