ITK inhibitors as an immunotherapeutic approach to colorectal cancer

Colorectal cancer CRC is the third most common form of cancer resulting in over half a million deaths each year Despite the use of chemotherapies and biologics the five year CRC survival rate is only a little over Immunotherapy is an exciting new line of attack that is particularly well suited for the treatment of CRC Immunotherapeutics are expected to be efficacious in treating genetically heterogeneous tumors and drug resistant tumors which make up a significant portion of CRC tumors In CRC patients Th immune cells induce a tolerant and angiogenic tumor environment correlating with poor prognosis while Th and CTL CD cells are associated with a tumor killing environment and correlate with survival Interleukin inducible T cell kinase ITK is a member of the Tec kinase family downstream of the T cell receptor and is involved in Th cell but not Th cell survival and activation Therefore selectively blocking ITK will inhibit Th cells while sparing Th and CTL CD cells While Ibrutinib a pan Tec kinase inhibitor blocking BTK ITK and TXK has shown promise in the clinic our approach specifically targets ITK thereby removing the negative effects of inhibiting TXK decreased Th response and BTK increased infection risk and bleeding In this SBIR Phase application we propose to develop the first ITK inhibitor drug candidate for the treatment of CRC We have developed an innovative kinase drug discovery platform KINect that exploits our proprietary kinase inhibitor library in the context of structure based drug design SBDD to rapidly identify and develop active drug like chemical cores into drug candidates Using this approach and our own ITK crystal structure we utilized our extensive drug development experience to identify a set of potent selective covalent and proprietary lead ITK inhibitor compounds that block Th cell activation We propose to further develop ITK drug candidates to test the central hypothesis that selective inhibitors of ITK will be efficacious immunotherapeutics for the treatment of CRC by inhibiting immunosuppressive Th cells while sparing Th and CD CTL cells thereby facilitating the anti tumor amplification alone or in combination with checkpoint inhibitors The proposed research focuses on the following specific aims Optimize the TXK selectivity and T cell activity of ITK inhibitor drug candidates as immunotherapeutics to treat CRC and Determine ITK inhibitor efficacy in murine in vivo models of Th function and CRC SBIR Phase studies will focus on generating additional preclinical in vivo CRC efficacy data as well as pharmaceutical pharmacokinetic and safety data advancing the program to IND and initiation of human Phase clinical evaluation in CRC patients Supporting studies will include genetically engineered mouse CRC models regulatory toxicology pharmacokinetics and drug product synthesis We anticipate a co development partnership license following Phase clinical studies with a deal value of andgt $ M Given the need for new CRC therapies the development of an effective ITK inhibitor drug will address a key unmet need and have a major medical impact Colorectal cancer is the third most common form of cancer in the U S resulting in over deaths a year To overcome this unmet medical need Confluence Life Sciences Inc will develop proprietary safe and more efficacious orally available small molecule inhibitors of ITK a kinase responsible for T cell differentiation and receptor activation to be used as an immunotherapeutic to treat this deadly disease