A NOVEL SMALL MOLECULE CX3CR1 ANTAGONIST HALTS METASTASIS

Project SummaryAbstractA NOVEL SMALL MOLECULE CX CRANTAGONIST HALTS METASTASIS Evidence in pre clinical and clinical settings suggests the involvement of chemokines in metastatic tumor cell disease spreadingWe have designed and synthesized the first novelpotentsmall molecule CX CRantagonist probeJMSJMSis a potent selective CX CRfunctional antagonistpERK ICnMChemotaxis ICnMJMSis effective in vivoas it potently blocks tumor cell seeding to the skeleton and slows metastatic progression in a mouse model of established metastasisThe improved advanced leadJMS FXpERK ICnMshows impressive survival data in a preliminaryweek in vivo efficacy studyand importantly appears to demonstrate an effective and safe survival outcomeSpecific aims of this proposal areSpecific AimSpecific AimIdentify a compound with improved liver microsome stability while maintaining good drug like propertiesGoalTo clearly provide Drug like property and selectivity assessment for the top analogsSpecific AimComplete full characterization of JMS FXto provide Development Candidate AssessmentGoalTo clearly assess Development candidate criteria for this advanced pre clinical lead compoundSpecific AimIdentification and characterization of a fast follow up to JMS FXGoalTo clearly assess Development candidate criteria for an advanced pre clinical follow up lead compoundAn inhibitor of metastatic dissemination will advance clinical practice and improve therapy by directly addressing tumor spreadingthe direct cause of mortality in patients with advanced diseaseSynergy of a CX CRantagonist and a chemotherapeutic is expected due to preventing CTCs from entering the sanctuary of the bone marrowEvidence shows that CX CRantagonism extends to oncology indications such as breast adenocarcinomaprostateepithelial ovarian carcinomapancreatic cancerand gliomaThusit is envisioned that an efficacious drug to treat metastatic progression would be widely applicable and have a significant impact on the morbidity and mortality associated with metastatic disease