MerTK is a receptor tyrosine kinase most prominently expressed in myeloid cells and known for its role in phagocytosis of early apoptotic cells and concomitant establishment of tolerogenic microenvironment. Hence, MerTK is thought to play a significant role in cancer immune evasion as, for example, a defining component of M2c-type tumor-associated macrophages (TAMs). Moreover, it has also been increasingly recognized that MerTK is overexpressed in a variety of malignant tumor cells, promoting the cancer cell survival, invasion, and treatment resistance. As such, it is anticipated that the cancer cell intrinsic and extrinsic effects might conspire to make MerTK a highly promising target for anticancer therapy. We describe herein an exquisitely selective series of MerTK inhibitors. A lead compound, XL1547, exhibited an IC50 of 1 nM against MerTK in an enzyme assay, with a greater than 300-fold selectivity over closely related AXL kinase (IC50 = 350 nM). In fact, MerTK was the only enzyme that was inhibited by XL1547 (> 99% at 100 nM) in the panel of 386 kinases (Reaction Biology Corp.; all others < 35%). X-ray crystal structure revealed a unique binding mode where the compound exploits a large back pocket next to the gatekeeper residue (known as a Type 1.5 binder). XL1547 potently inhibited autophosphorylation as well as the viability of engineered BaF3(CD8:MerTK) cells (GI50 = 230 nM) with little toxicity. Extensive medicinal chemistry efforts yielded a more advanced compound SA3686 with at least 10-fold improvement in potency. More importantly, it displayed a pharmacokinetic profile suitable for oral dosing. Indeed, SA3686 was highly efficacious in vivo in an allograft tumor model of subcutaneously implanted Ba/F3(CD8:MerTK) cells. [SA3686 is being tested in multiple other in vivo models at the time of abstract submission]. In summary, we have identified an essentially mono-selective MerTK inhibitor series that will help delineate the biology of MerTK-specific inhibition and hopefully validate the translational potential of MerTK as a therapeutic target for human diseases including cancer.

Citation Format: Taeyoung Yoon, Joon-Ho Sheen, Seong Jin Park, Jin Kwan Kim, Hadong Kim, Eun-Jung Kim, Munjin Kwon, Hyung Ki Lee, Okyung Lee, Youngjee Jeong, Ki Moon Ryu, Miyeon Jang, Jae-Sung Hwang. Discovery of exquisitely selective MerTK inhibitors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A168.