No abstract

SummaryIn response to stress, cancer cells generate nutrients and energy through a cellular recycling process called autophagy, which can promote survival and tumor progression. Accordingly, autophagy inhibition has emerged as a potential cancer treatment strategy. Inhibitors targeting ULK1, an essential and early autophagy regulator, have provided proof of concept for targeting this kinase to inhibit autophagy; however, these are limited individually in their potency, selectivity, or cellular activity. In this study, we report two small molecule ULK1 inhibitors, ULK-100 and ULK-101, and establish superior potency and selectivity over a noteworthy published inhibitor. Moreover, we show that ULK-101 suppresses autophagy induction and autophagic flux in response to different stimuli. Finally, we use ULK-101 to demonstrate that ULK1 inhibition sensitizes KRAS mutant lung cancer cells to nutrient stress. ULK-101 represents a powerful molecular tool to study the role of autophagy in cancer cells and to evaluate the therapeutic potential of autophagy inhibition.

Clarification of the mechanisms of hydrogen release and uptake in transition-metal-doped sodium alanate, NaAlH 4, a prototypical highdensity complex hydride, has fundamental importance for the development of improved hydrogen-storage materials. In this and most other modern hydrogen-storage materials, H 2 release and uptake are accompanied by long-range diffusion of metal species. Using firstprinciples density-functional theory calculations, we have determined that the activation energy for Al mass transport via AlH3 vacancies is Q ‫؍‬ 85 kJ/mol⅐H 2, which is in excellent agreement with experimentally measured activation energies in Ti-catalyzed NaAlH 4. The activation energy for an alternate decomposition mechanism via NaH vacancies is found to be significantly higher: Q ‫؍‬ 112 kJ/mol⅐H 2. Our results suggest that bulk diffusion of Al species is the rate-limiting step in the dehydrogenation of Ti-doped samples of NaAlH4 and that the much higher activation energies measured for uncatalyzed samples are controlled by other processes, such as breaking up of AlH 4 ؊ complexes, formation/dissociation of H2 molecules, and/or nucleation of the product phases.density-functional theory ͉ hydrogen storage ͉ kinetics ͉ metal hydride ͉ molecular dynamics

Drugging large protein pockets is a challenge due to the need for higher molecular weight ligands, which generally possess undesirable physicochemical properties. In this communication, we highlight a strategy leveraging small molecule active site dimers to inhibit the large symmetric binding pocket in the STING protein. By taking advantage of the 2:1 binding stoichiometry, maximal buried interaction with STING protein can be achieved while maintaining the ligand physicochemical properties necessary for oral exposure. This mode of binding requires unique considerations for potency optimization including simultaneous optimization of protein−ligand as well as ligand−ligand interactions. Successful implementation of this strategy led to the identification of 18, which exhibits good oral exposure, slow binding kinetics, and functional inhibition of STING-mediated cytokine release.