Design, Synthesis, and Biological Evaluation of Potent and Selective PROTAC Degraders of Oncogenic KRAS.

KRAS, the most frequent KRAS oncogenic mutation, is a promising target for cancer therapy. Herein, we report the design, synthesis, and biological evaluation of a series of KRAS PROTACs by connecting the analogues of MRTX1133 and the VHL ligand. Structural modifications of the linker moiety and KRAS inhibitor part suggested a critical role of membrane permeability in the degradation activity of the KRAS PROTACs.

Learning protein fitness landscapes with deep mutational scanning data from multiple sources.

One of the key points of machine learning-assisted directed evolution (MLDE) is the accurate learning of the fitness landscape, a conceptual mapping from sequence variants to the desired function. Here, we describe a multi-protein training scheme that leverages the existing deep mutational scanning data from diverse proteins to aid in understanding the fitness landscape of a new protein. Proof-of-concept trials are designed to validate this training scheme in three aspects: random and positional extrapolation for single-variant effects, zero-shot fitness predictions for new proteins, and extrapolation for higher-order variant effects from single-variant effects.

Design, Synthesis, and Bioevaluation of Pyrido[2,3-]pyrimidin-7-ones as Potent SOS1 Inhibitors.

The use of small molecular modulators to target the guanine nucleotide exchange factor SOS1 has been demonstrated to be a promising strategy for the treatment of various KRAS-driven cancers. In the present study, we designed and synthesized a series of new SOS1 inhibitors with the pyrido[2,3-]pyrimidin-7-one scaffold. One representative compound showed comparable activities to the reported SOS1 inhibitor BI-3406 in both the biochemical assay and the 3-D cell growth inhibition assay.