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A novel and proprietary molecular scaffold has been developed usingcomputational modeling allowing for the design of pan-PI3 kinase inhibitors aswell as isoform-selective small molecule PI3 kinase inhibitors. The scaffoldalso allows for the design of compounds that can be administered orally orintravenously. Of 50 compounds identified, SF2523 and SF2506 have been chosenfor additional evaluation based on their ability to inhibit multiple kinases,including PI3K, mTOR, DNA-PK and PIM-1. SF2523 and SF2506 also havedramatically increased potency relative to the well-known PI3 kinase inhibitorLY294002. Both inhibitors demonstrated the ability to significantly induceapoptosis in a renal cell carcinoma cell line (786-0).
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Evaluation of SF2523 in a 232 kinase panel screen showed that the compoundselectively and potently inhibits key cancer kinase targets, including mTOR,DNA-PK, PIM-1 and PI3K. SF2523 demonstrated potent anticancer proliferationactivity across a broad range of 18 cancer cell lines representing solidtumors (lung, pancreatic, prostate, colon, breast, brain, ovarian, renal andmelanoma) and hematological malignancies (AML, CML and multiple myeloma).Notably, SF2523 inhibited proliferation in multiple cell lines with KRASmutations, including HCT116-colon, A549 lung, BXPC3 pancreatic and RPMI8226myeloma cell lines. Colorectal cancer patients with KRAS mutations have beenidentified as less likely to respond to EGFR inhibitors (ASCO 08). Newcompounds with activity against KRAS mutations are being actively pursued toaddress the unmet medical need.
In vivo testing of SF2523 in renal cell carcinoma (RCC) mouse xenograftmodels demonstrated 81 percent tumor growth inhibition. SF2506 testingresulted in 93 percent tumor growth reduction in the same model.
"Semafore's proprietary kinase scaffold and our new multi-targeted kinaseinhibitors add significant value to our pipeline," said Dr. Dennis McKeever,Semafore's Chief Executive Officer. "In addition to inhibiting all Class Iisoforms of PI3K, our compounds SF2506 and SF2523 block additional key kinaseswhich is in keeping with the multi-targeting philosophy behind other recentsuccessful molecularly targeted agents."
About Semafore
Semafore is a clinical stage drug discovery and development companyfocused on small molecule modulators of the PI3 kinase and PTEN cell signalingpathway, a promising target pathway for multiple disorders, including thecompany's focus -- cancer. Semafore is a leader in the development of PI3Kinhibitors and one of the first biopharmaceutical companies to focus on bothPI3K and PTEN. The company has successfully discovered and is developing aportfolio of drug candidates addressing these targets.
About SF1126
There is a strong and significant biological rationale for developing PI3kinase inhibitors to treat cancer. Phosphoinositide 3-kinase (PI3K) is thegate keeper of one of the major pathways of intracellular signal transductionthat regulates cell growth, proliferation, angiogenesis, migration,differentiation, and survival. Dysregulation of the PI3K signaling pathway isbelieved to play an integral role in the genesis of many cancers includingboth solid tumors and hematologic malignancies. Cancer research andpharmaceutical drug development efforts have been aimed at discovering anddeveloping therapeutics that inhibit PI3K with the hope of controlling cancercell division, angiogenesis (the formation of new blood vessels for cancergrowth), proliferation and metastasis. Semafore's innovative PI3K inhibitor,SF1126, promises such hope for canc
