AC708

CSF1R Program: Selective Kinase Inhibitors for Oncology and Inflammation

Our lead compound in the program is a potent and exquisitely selective small molecule compound, AC708, that inhibits CSF1R.

Signaling through CSF1R controls the activation, proliferation and survival of macrophages, key mediators of immune system function.

The tumor microenvironment is increasingly understood to be a source of therapeutic targets for the treatment of cancer, and tumor associated macrophages, or TAMs, are thought to play a key role. TAMs, through cellular signaling, can promote angiogenesis (blood vessel formation in tumors), tumor survival and metastasis, and may confer resistance to current therapies. TAMs are dependent on CSF-1 (a cytokine that signals through CSF1R), and we believe that a drug that inhibits CSF1R could limit the influence of TAMs on the tumor microenvironment, and could be complementary and augment current cancer therapies. Over-activation of macrophages is believed to play a role in conditions such as rheumatoid arthritis, inflammatory bowel diseases, lupus nephritis, diabetic nephropathy, atherosclerosis, and even conditions such as obesity.

CSF1R is a member of the same kinase family as FLT3, cKIT, and PDGFR, and all share a highly similar structure. While the CSF1R kinase has been a target of interest in the pharmaceutical industry for several years, a key challenge has been the identification of inhibitors with sufficient selectivity for CSF1R (and minimal to no off-target activity on FLT3, cKit and PDGFR) and there are currently no approved therapies that specifically target CSF1R. We believe that a CSF1R inhibitor that also provides potent inhibition of FLT3 and/or cKIT may result in myelosuppression, a side effect which would limit dosing in oncology indications and be unacceptablein non-oncology indications. We believe there is therapeutic potential for our CSF1R inhibitor program in oncology and/or autoimmune and inflammatory diseases due to maximized selectivity and potency on CSF1R and minimized off-target activity.

We have discovered and are developing a potent compound, AC708, that is exquisitely selective for CSF1R, including significantly reduced activity against FLT3, cKIT and PDGFR. Characterization of this preclinical compound in in vitro and in vivo studies has demonstrated potent inhibition of CSF1R and inhibition of macrophage activity and proliferation. IND-enabling toxicology studies have shown AC708 to be generally well tolerated at exposures higher than what we believe will be necessary to achieve a therapeutic response in patients. We are expanding our pre-clinical studies of AC708 in oncology disease models to better define our plans for our Phase 1 and Phase 2 clinical trials. We plan to further develop this program independently or in collaboration with a strategic partner.