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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.

For poorly soluble drugs formulated as amorphous solid dispersions (ASDs), fast and complete release with the generation of drug-rich colloidal particles is beneficial for optimizing drug absorption. However, this ideal dissolution profile can only be achieved when the drug releases at the same normalized rate as the polymer, also known as congruent release. This phenomenon only occurs when the drug loading (DL) is below a certain value. The maximal DL at which congruent release occurs is defined as the limit of congruency (LoC). The purpose of this study was to investigate the relationship between drug chemical structure and LoC for PVPVA-based ASDs. The compounds investigated shared a common scaffold substituted with different functional groups, capable of forming hydrogen bonds only, halogen bonds only, both hydrogen and halogen bonds, or nonspecific interactions only with the polymer. Intermolecular interactions were studied and confirmed by X-ray photoelectron spectroscopy and infrared spectroscopy. The release rates of ASDs with different DLs were investigated using surface area normalized dissolution. ASDs with hydrogen bond formation between the drug and polymer had lower LoCs, while compounds that were only able to form halogen bonds or nonspecific interactions with the polymer achieved considerably higher LoCs. This study highlights the impact of different types of drug–polymer interactions on ASD dissolution performance, providing insights into the role of drug and polymer chemical structures on the LoC and ASD performance in general.

Supersaturating formulations such as amorphous solid dispersions (ASDs) can lead to solution concentrations much higher than the crystalline solubility achieving enhanced oral bioavailability of poorly aqueous soluble compounds. However, they can potentially crystallize with a loss of their solubility advantage. Various polymers have been extensively used to delay crystallization. Increasingly, surfactants are being incorporated into ASDs to improve processing and dissolution performance. While the effect of polymers has been widely studied, the impact of surfactants on crystallization has not yet been explored to the same extent. In this work, the effect of a commonly used surfactant, sodium dodecyl sulfate (SDS) on the nucleation induction time (NIT) of a model compound, atazanavir (ATZ) was studied. NITs of supersaturated solutions with the same supersaturation ratio (SR) were measured in the presence of various SDS concentrations, ranging from well below the critical micelle concentration (CMC) to well above CMC, in order to evaluate the impacts of monomeric SDS molecules versus SDS micelles. SDS was found to promote crystallization at a certain minimum SDS concentration (critical hemimicelle concentration, CHMC). Further, no additional decrease in NIT was observed once the CMC of SDS was exceeded. To elucidate the mechanism of crystallization induction, fluorescence studies were carried out with crystal slurries. Fluorescence data strongly suggest that SDS hemimicelles present on the nucleus/crystal surface are responsible for the observed shortened induction times in ATZ nucleation. These adsorbed SDS hemimicelles can reduce the crystal–water interfacial energy, promoting nucleation. The combined effect of polymer and surfactant, using concentrations relevant to those produced upon ASD dissolution, was also studied. In the absence of SDS, the polymers inhibited detectable nucleation for >1000 min. In the presence of SDS, cellulosic polymers such as hydroxypropyl methyl cellulose 606 (HPMC-606) and hydroxypropyl methyl cellulose acetate succinate MF (HPMCAS-MF) maintained a similar level of inhibitory effect, whereas polyvinylpyrrolidone/vinyl acetate (PVPVA) lost some of its inhibitory effect.