SignalRx Pharmaceuticals Announces Breakthrough Results on Novel Anti-Cancer Dual PI3K-BRD4 Inhibition Paradigm in PNAS Publication

On January 31, 2018 SignalRx Pharmaceuticals Inc., a clinical-stage company focused on developing new and more effective oncology drugs with designed multiple target-selected inhibition profiles, reported the publication of key research in the journal Proceedings of the National Academy of Sciences (doi: 10.1073/pnas.1613091114 PNAS January 30, 2017) (Press release, SignalRx, JAN 31, 2017, [SID1234527325]).

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SignalRx Pharmaceuticals Inc., in collaboration with researchers at the University of California, San Diego School of Medicine and Moores Cancer Center, led by Dr. Donald L. Durden, Professor and Associate Director of Pediatric Oncology at the Moores UCSD Cancer Center, and senior scientific advisor at SignalRx along with Dr. Tatiana Kutateladze, Professor at the University Colorado, Department of Pharmacology, report on key preclinical findings using the small molecule SF2523 designed to inhibit the key cancer targets PI3K and BRD4.

Key results include:

Designed dual inhibition: The dual inhibitor SF2523 inhibits the acetyl-lysine binding of the epigenetic reader protein BRD4 as well the kinase activity of PI3K thus simultaneously disrupting two orthogonal cancer driving mechanisms that promote undesirable effects from the oncogene MYC which is responsible for activating the immuno-oncology targets CD47 and PD-L1. X-ray crystal structures of SF2523 bound to BRD4 isoforms were obtained and are consistent with in silico modeling predictions and thus provide insights for further investigations.
Mode of action: SF2523 blocks both PI3K and BRD4 signaling in vitro and in vivo promoting maximal MYC down-regulation.
Anticancer activity in vivo: SF2523 markedly inhibits cancer cell growth and metastasis in mouse models of neuroblastoma and an orthotopic pancreatic metastatic tumor model.
Safe in vivo profile: Most importantly, the dual PI3K/BRD4 inhibitor SF2523 is dramatically much safer in vivo than the administration of two separate inhibitors in combination (PI3K and BRD4). This proof of concept shows that designing 1 drug with the attributes of 2 distinct drugs (2 drugs in 1) can eliminate or significantly reduce unwanted added toxicity of combination drugs providing an exciting opportunity for the exploration of more sophisticated combinations for maximal anticancer efficacy.
SF2523, as discussed in the manuscript, inhibits phosphatidylinositol 3-kinase (PI3K) which, in addition to drive cancer on its own, also inhibits the epigenetic reader bromodomain-containing protein 4 (BRD4). This new anticancer paradigm harnesses the synergistic impact of inhibiting simultaneously PI3K and BRD4 to maximally inhibit MYC activity by enhancing MYC degradation (PI3K inhibition) and blocking MYC production (inhibition of MYC transcription via BRD4 inhibition). MYC inhibition is an important oncology outcome of this new anticancer paradigm because inactivation of MYC down-regulates immuno-oncology targets CD47 and PD-L1. This down-regulation offers a novel immune-oncology approach alone or in combination with checkpoint inhibitors.

SF2523 has arisen from SignalRx’s platform technology for cancer therapeutics that enables the engineering of one small molecule to inhibit two or more molecular targets in the cancer and stromal cell for maximum anticancer efficacy and unprecedented safety in vivo. While most anti-cancer drugs are made with a single cancer target in mind, the lead compound SF2523 was designed to inhibit two or more key orthogonal signaling biomolecules simultaneously within the cancer cell.

The cancer targets for this new technology approach are selected based on forward genetics and the discovery of important cancer synthetic lethalities for therapeutic exploitation. This effective engineering approach is in contrast to the industry paradigm which relies on random screening efforts of large collections of compounds hoping to find interesting dual-target activities. With SignalRx’s technology, it is possible now to molecularly design dual and triple inhibitory chemotypes for maximum in vivo antitumor activity while maintaining a safety advantage over using combinations of drugs to attempt similar attacks on cancer targets.

SignalRx is seeking a partner to accelerate the development of SF2523 and SF2535 into first-in-man clinical trials based on the promising profile of its PI3K/BRD4 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 such as kinome adaptation mediated by BRD4.