Discovery of Tivumecirnon (FLX475), a Potent and Selective CCR4 Antagonist That Inhibits the Migration of Immunosuppressive Regulatory T Cells into the Tumor Microenvironment to Restore Antitumor Immunity.

The recruitment of immunosuppressive regulatory T cells (Treg) into the tumor microenvironment (TME) dampens the antitumor immune response and is thought to be a key driver in tumor immune evasion. Treg express the CC chemokine receptor 4 (CCR4) broadly and are recruited to the TME through interactions with its specific chemokines CCL17 and CCL22 that are elevated in many cancer types. The selective blocking of Treg migration to the TME has the potential to restore antitumor immunity and potentiate the efficacy of a variety of conventional and immuno-therapies. We have developed novel CCR4 antagonist small molecules that selectively and potently inhibit the migration of Treg to the TME (hTreg CTX IC50: 27 nM) and have culminated in our clinical candidate (14, FLX475, Tivumecirnon). The discovery of this potent, selective, and orally bioavailable CCR4 antagonist and its characterization in several preclinical models is described herein.