On April 3, 2017 SignalRx Pharmaceuticals Inc., focused on developing novel small-molecule cancer therapeutics targeting key orthogonal and synergistic oncotargets, reported the upcoming presentation of scientific data on the company’s triple PI3K/CDK4-6/BRD4 inhibitor program and first-in-class triple inhibitor SRX3177 (Press release, SignalRx, APR 3, 2017, http://www.ireachcontent.com/news-releases/signalrx-to-present-at-the-aacr-annual-meeting-on-its-first-in-class-triple-pi3kcdk4-6brd4-inhibitor-srx3177-for-treating-cancer-617971313.html [SID1234527324]). The poster presentation by Dr. Donald L. Durden, MD, PhD, senior scientific advisor for SignalRx, will be poster #LB-298 at the April 5th late breaking poster session at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in Washington, DC.
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SRX3177 is developed on the rationale that concurrent PI3K inhibition can prevent resistance to CDK4/6 inhibition, and combined CDK4/6 and PI3K inhibition leads to synthetic lethality reported in a number of cancer types, including breast cancer and mantle cell lymphoma, and blocking the chromatin reader protein BRD4 downregulates MYC and cyclin D1 transcription, further promoting cell cycle arrest in G1.
The presentation will describe the discovery and early development of the molecularly designed small-molecule triple inhibitor SRX3177. Key highlights to be presented include:
SRX3177’s potent in vitro enzymatic inhibition profile (IC50: CDK4 = 2.54 nM, CDK6 = 3.26 nM; PI3Kα = 79.3 nM, PI3Kδ = 83.4 nM; BRD4-BD1 = 32.9 nM, BRD4-BD2 = 88.8 nM).
SRX3177 rational design based on thieno-pyranone scaffold and target modeling.
Up to 82-fold more potent than palbociclib in a panel of mantle cell lymphoma, neuroblastoma, and hepatocellular carcinoma cell lines.
5-Fold more potent in cancer cells than combination of BKM120 (PI3K inhibitor) + palbociclib (CDK4/6 inhibitor) + JQ1 (BRD4 inhibitor).
40-Fold less toxic to normal epithelial cells than combination of BKM120 + palbociclib + JQ1.
Cell cycle arrest and apoptosis induction with proven mode of action (p-AKT, p-Rb, chromatin release).
SignalRx is also announcing that it is seeking partnering opportunities to accelerate the development of this program and its PI3K-BRD4 program to advance novel small molecules into first-in-man clinical trials based on the promising profile of its inhibitors shown so far. Since these are single molecules with a single PK/PD and toxicity profile, there is a great opportunity to develop them as single therapeutics and streamline their development in combination therapies focused on companion diagnostics built around synthetic lethality discoveries in human cancers.