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Inhibition of the receptor tyrosine kinase MerTK by small molecules has the potential to augment the immune response to tumors. Potent, selective inhibitors with high levels of in vivotarget engagement are needed to fully evaluate the potential use of MerTK inhibitors as cancer therapeutics. We report the discovery and optimization of a series of pyrazinamide-based type 1.5 MerTK inhibitors bearing an azetidine-benzoxazole substituent. Compound 31potently engages the target in vivoand demonstrates single agent activity in the immune-driven MC-38 murine syngeneic tumor model.

TAM receptor tyrosine kinases have emerged as promising therapeutic targets for cancer treatment due to their roles in both tumor intrinsic survival mechanisms and suppression of antitumor immunity within the tumor microenvironment. Inhibiting MerTK and Axl selectively is believed to hinder cancer cell survival, reverse the protumor myeloid phenotype, and suppress efferocytosis, thereby eliciting an antitumor immune response. In this study, we present the discovery of A-910, a highly potent and selective dual MerTK/Axl inhibitor, achieved through a structure-based medicinal chemistry campaign. The lead compound exhibits favorable oral bioavailability, exceptional kinome selectivity, and significantly improved in vivo target engagement. These findings support the use of A-910as an orally bioavailable in vivo tool compound for investigating the immunotherapy potential of dual MerTK/Axl inhibition.

ABSTRACTA total of 336 Streptococcus pyogenesisolates recently recovered from patients with pharyngitis from 13 countries were characterized by emmtyping and riboprinting using an automated Riboprinter (Dupont/Qualicon) based on the patterns produced by three restriction enzymes, EcoRI, PstI, and HindIII. Three enzymes were necessary to increase the discrimination of ribogroups formed by each enzyme. A total of 40 ribogroups and 38 emmsequences (not counting allelic variations) were identified. Multilocus sequence typing was performed on a sampling of the isolates, and those results were consistent with those of both emmtyping and ribotyping. Correlations were observed among all three methods.

ABSTRACTThe regulatory regions of 52 erm(A) [formerly erm(TR)] clinical Streptococcus pyogenesisolates were studied. Differences in the upstream regulatory region of erm(A) correlated with macrolide/lincosamide resistance patterns. Nine macrolide/lincosamide/streptogramin B-resistant isolates had changes in the leader sequence of erm(A) including base changes, insertions, or deletions. Isolates were also emmtyped.