On April 25, 2017 SignalRx Pharmaceuticals Inc., a clinical-stage company developing novel small-molecules therapeutics to inhibit key orthogonal and synergistic oncotargets for the treatment of cancer, reported the presentation of its novel triple PI3K/CDK4-6/BRD4 inhibitor program and first-in-class triple inhibitor SRX3177 (Press release, SignalRx, APR 25, 2017, http://www.ireachcontent.com/news-releases/signalrx-to-present-at-the-12th-annual-drug-discovery-chemistry-2017-meeting-on-its-first-in-class-triple-pi3kcdk4-6brd4-inhibitor-srx3177-for-treating-cancer-620334743.html [SID1234527323]). The presentation by Donald L. Durden, MD, PhD, senior scientific advisor for SignalRx, will be at 5pm on Tuesday April 25th, 2017, in the Fragment-Based Drug Discovery session at the Drug Discovery Chemistry 2017 meeting in San Diego, CA.

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Using SignalRx’s proprietary CRIMP technology platform, the company developed SRX3177 to simultaneously inhibit three key cancer-driving oncotargets: PI3K, CDK4-6 and BRD4. Cancer biology has demonstrated that PI3K inhibition abrogates resistance to CDK4/6 inhibition, and the combined CDK4/6 and PI3K inhibition leads to synthetic lethality in a number of cancer types (e.g., breast cancer, mantle cell lymphoma). BRD4 is a key epigenetic target that drives many cancers and the transcription of cyclin D1 and MYC, the latter in turn drives the immuno-oncology targets CD47 and PD-L1. The simultaneous inhibition of PI3K/CDK4-6/BRD4 with a single molecule presents the opportunity to deliver synthetic lethality to cancers dependent on these onco-pathways where kinase resistance is also developed.

The presentation will cover the discovery and in silico design of the small-molecule triple inhibitor SRX3177. Key highlights to be presented include:

Potent target profile (IC50: CDK4/6 = 2-3 nM; PI3Kα/δ @ 80 nM, BRD4-BD1 = 33 nM, BRD4-BD2 = 89 nM).
In silico design.
Cell cycle arrest and apoptosis induction.
Biomarkers (p-AKT, p-Rb, BRD4-chromatin release).
82-Fold more potent than FDA-approved palbociclib against mantle cell lymphoma, neuroblastoma, and hepatocellular carcinoma cells.
5-Fold more potent in cancer cells than combination of palbociclib (CDK4/6 inhibitor) + BKM120 (PI3K inhibitor) + JQ1 (BRD4 inhibitor).
Much safer with 40-fold less toxicity to normal epithelial cells vs palbociclib + BKM120 + JQ1.
SignalRx is also seeking partnering opportunities to accelerate the development of its programs and advance novel anticancer therapeutics into first-in-man clinical trials based on the promising profile and mode of action of its inhibitors. Since these are single molecules with a single PK/PD and toxicity profile, there is a great opportunity to streamline their development alone and in combination therapies.