On May 19, 2015 SignalRx Pharmaceuticals Inc., focused on developing more effective oncology drugs though molecular design imparting selective multiple target inhibition, reported that it has received non-dilutive funding to advance the preclinical development of unique small molecule inhibitors designed to inhibit multiple critical cancer targets (Press release, SignalRx, MAY 19, 2015, http://www.ireachcontent.com/news-releases/signalrx-pharmaceuticals-inc-awarded-sttr-grant-from-the-national-institutes-of-health-for-development-of-dual-pi3-kinasebromodomain-inhibitors-as-anticancer-agents-504347611.html [SID1234527329]).
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SignalRx was awarded a Phase 1 Small Business Technology Transfer Research (STTR) grant from the National Cancer Institute (NCI), a division of the National Institutes of Health (NIH), in support of the preclinical development of novel small molecules that simultaneously inhibit two key cancer targets: PI3kinase (PI3K) and the bromodomain protein BRD4. The principal investigator on the STTR grant is SignalRx’s scientific advisor Dr. Donald Durden, MD, PhD who also serves as the academic collaborator for the grant while in his capacity as the Associate Director for Pediatric Oncology at the Moores UCSD Cancer Center at the University of California, San Diego.
Inhibiting the key cancer promoting transcription factor MYC (both cMYC and MYCN) is vigorously pursued since this inactivates many genes that drive cancer cell growth and proliferation. To date, small molecule inhibitors of MYC have been elusive. SignalRx’s innovative approach is to indirectly orthogonally diminish the activity of MYC by enhancing its degradation using PI3K inhibition combined with simultaneous blocking the transcription of the gene producing MYC via inhibition of the bromodomain protein BRD4—all resulting from a single molecule. Combination treatments are necessary in cancer, and there is an ever increasing need for more complex combinations to inhibit multiple targets to maximize efficacy. However, combining single-action drugs becomes unfeasible due to prohibitive costs when combining expensive targeted therapies in addition to being a barrier to early clinical evaluation of such complex combinations of drugs. SignalRx provides proprietary single molecules designed to inhibit multiple specific key cancer targets and thus strive for more cost-effective efficacy-improved therapeutics.
SignalRx has discovered and patented a novel molecular scaffold whose members are potent PI3K inhibitors designed to simultaneously inhibit the bromodomain protein BRD4. These dual PI3K/BRD4 inhibitors are the subject of the awarded grant along with the development of molecular modeling tools to help facilitate the structure activity relationships now under study. Preliminary results of these dual PI3K/BRD4 inhibitors have demonstrated in vivo efficacy without toxicity in several mouse cancer models, confirming the advantage of circumventing potential safety concerns arising from the use of multiple drugs. Moreover, successful proof of concept by showing knockdown of both the PI3K pathway and MYC levels was confirmed from the examination of excised mouse tumors 4 hours after administration of a dual PI3K/BRD4 inhibitor.
"The STTR grant award by the NCI to develop a single molecule that inhibits both PI3K and BRD4 represents a major step forward in translating new findings in cancer biology to maximize the activity and durability of effect in new anticancer agents" said Donald L. Durden, MD, PhD. "This approach, in addition to challenging the current dogma of single-targeted oncology drugs, has promise to maximally block the tumor suppressor gene MYC which drives many cancers including CLL, medulloblastoma, multiple myeloma, and high-grade epithelial ovarian cancers exhibiting elevated MYCN expression."