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Semafore Broadens Pipeline With Multi-Targeted Kinase Inhibitors
Date:8/26/2008

INDIANAPOLIS, Aug. 26 /PRNewswire/ -- Semafore Pharmaceuticals Inc. presented data at the Seventh International Congress on Targeted Therapies in Cancer in Washington, D.C., announcing the discovery of novel multi-targeted kinase inhibitors that demonstrate significant anticancer activity in preclinical studies.

A novel and proprietary molecular scaffold has been developed using computational modeling allowing for the design of pan-PI3 kinase inhibitors as well as isoform-selective small molecule PI3 kinase inhibitors. The scaffold also allows for the design of compounds that can be administered orally or intravenously. Of 50 compounds identified, SF2523 and SF2506 have been chosen for additional evaluation based on their ability to inhibit multiple kinases, including PI3K, mTOR, DNA-PK and PIM-1. SF2523 and SF2506 also have dramatically increased potency relative to the well-known PI3 kinase inhibitor LY294002. Both inhibitors demonstrated the ability to significantly induce apoptosis in a renal cell carcinoma cell line (786-0).

Evaluation of SF2523 in a 232 kinase panel screen showed that the compound selectively and potently inhibits key cancer kinase targets, including mTOR, DNA-PK, PIM-1 and PI3K. SF2523 demonstrated potent anticancer proliferation activity across a broad range of 18 cancer cell lines representing solid tumors (lung, pancreatic, prostate, colon, breast, brain, ovarian, renal and melanoma) and hematological malignancies (AML, CML and multiple myeloma). Notably, SF2523 inhibited proliferation in multiple cell lines with KRAS mutations, including HCT116-colon, A549 lung, BXPC3 pancreatic and RPMI8226 myeloma cell lines. Colorectal cancer patients with KRAS mutations have been identified as less likely to respond to EGFR inhibitors (ASCO 08). New compounds with activity against KRAS mutations are being actively pursued to address the unmet medical need.

In vivo testing of SF2523 in renal cell carcinoma (RCC) mouse xenogr
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SOURCE Semafore Pharmaceuticals Inc.
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