Dark kinases are a group of 160 proteins with poorly understood biological functions, resulting in a scarcity of tool compounds that could serve as starting points for drug discovery. We employ a multi-model deep learning approach to screen for novel inhibitors targeting dark kinases. We demonstrate that our method identifies molecules that engage these kinases across various active-site conformational states, thereby broadening the exploration of the kinase inhibitor chemical space.

The inhibition of kinases has been pursued by the pharmaceutical industry for over 20 years. We report Dark Kinase Allostery Atlas which is a systematic collection of binding hot spots located at sites on the entire human kinome, with the focus on dark kinases. The hot spots are identified by FTMap, a computational analogue of experimental fragment screening. The ensemble is sampled by a combination of physics and AlphaFold-based sampling.

The ROCK2 signaling pathway has been implicated in multiple therapeutic areas. Graviton’s GV101 is a potent, selective and best-in-class ROCK2 inhibitor. Our data in a hypertension-accelerated animal model demonstrate that GV101 treatment improves insulin sensitivity and reduces the plasma glucose and HbA1c levels. GV101 also reversed kidney fibrosis, especially glomerulosclerosis. This was illustrated with AI-powered pathological analysis of PAS-stained kidney sections. In addition, GV101 reduced macrophage infiltration and prevented the buildup of kidney injury molecules.

We have developed a groundbreaking approach by identifying a new allosteric modulation mechanism of NEK7. This modulation interrupts the vital interaction between NEK7 and NLRP3, effectively preventing the formation and function of the NLRP3 inflammasome, a major contributor to inflammatory and autoimmune diseases. These findings present a promising therapeutic strategy for effectively managing complex immune responses and inflammation.

PTK6/Brk was reported as an oncogenic driver in several tumor types, and in some cancer types, PTK6 non-catalytic functions play key roles in oncogenic activities. We present the discovery of novel PROTAC degrader—MS105—which potently downregulates PTK6 level, and induces expression of Bim and apoptosis of cancer cells. Taken together, our studies suggest PTK6 degrader could provide a preferred approach to clinically targeting PTK6 in cancer.

I will describe the synthesis of sulfonyl-triazoles as a new phenol-reactive group for covalent modification of tyrosine and lysine residues on proteins through sulfur-triazole exchange (SuTEx) chemistry. The reactivity of SuTEx chemistry is highly tunable, which can facilitate optimization of potent and selective binders to orthosteric and allosteric sites on kinases. I will conclude my talk by describing efforts to use lead SuTEx inhibitors for modulating kinase function in cells.

Proteolysis-targeting chimeras (PROTACs) offer the ability to drive degradation of kinases more selectively and efficaciously, relative to conventional small molecules. Discerning compound engagement with the kinome is challenging due to low expression levels of kinases but is necessary to compare the effects of PROTACs to corresponding small molecules. We present a kinase enrichment strategy implementing reverse competition to differentiate between small molecule binding and PROTAC binding on the kinome.