Identification of a Potent and Selective Focal Adhesion Kinase Proteolysis Targeting Chimera: Targeting Noncatalytic Functions of Focal Adhesion Kinase to Facilitate Antitumor Immunity.

Focal adhesion kinase (FAK) has emerged as a promising therapeutic target since its pivotal involvement in tumorigenesis. However, FAK inhibitors exhibit limited efficacy in suppressing FAK's noncatalytic functions, potentially compromising their therapeutic outcomes. Herein, we developed a series of FAK PROTACs derived from our previously characterized FAK inhibitor .

Discovery of a Potent FLT3 Inhibitor ()-4-(3-(3-Fluoro-4-(morpholinomethyl)styryl)-1-indazol-6-yl)pyridin-2-amine for the Treatment of Acute Myeloid Leukemia with Multiple FLT3 Mutations.

Targeting FLT3 genetic alterations has emerged as a promising therapeutic approach for AML. However, the rapid emergence of resistance to FLT3 inhibitors has severely curtailed their clinical utility. Herein, we developed a series of ()-4-(3-arylvinyl-1-indazol-6-yl)pyridin-2-amine derivatives to overcome FLT3 resistance mutations.

Design, synthesis and antitumor activity of a novel FGFR2-selective degrader to overcome resistance of the FGFR2 gatekeeper mutation based on a pan-FGFR inhibitor.

Aberrant activation of fibroblast growth factor receptors (FGFRs) contributes to the development and progression of multiple types of cancer. Although many FGFR inhibitors have been approved by the FDA, their long-term therapeutic efficacy is hampered by acquired resistance to gatekeeper mutations and low subtype selectivity. FGFR2 has been found to be frequently amplified or mutated in many tumors.

Discovery of a first-in-class degrader for the protein arginine methyltransferase 6 (PRMT6).

PRMT6 is a member of the protein arginine methyltransferase family, which participates in a variety of physical processes and plays an important role in the occurrence and development of tumors. Using small molecules to design and synthesize targeted protein degraders is a new strategy for drug development. Here, we report the first-in-class degrader SKLB-0124 for PRMT6 based on the hydrophobic tagging (HyT) method.

Comparison of Dural Graft Types and Graft Fixation Methods in Chiari Malformation Type I Decompression Surgery.

Objective: Suboccipital decompression with duraplasty is being increasingly accepted for treating patients with Chiari malformation type I (CM-1). To date, the optimal duraplasty for CM-I has not been delineated. This study aims to compare the clinical and radiologic effects of duraplasty performed using 2 types of grafts and 2 graft fixation methods in 3 combinations.

Different Doses of Clazosentan for Aneurismal Subarachnoid Hemorrhage: A Meta-Analysis of Randomized Controlled Trials.

Clazosentan therapy has been found to be effective in reducing the incidence of vasospasm after aneurismal subarachnoid hemorrhage (aSAH). The objective of this meta-analysis was to determine whether different doses of clazosentan treatment significantly reduced the incidence of delayed ischemic neurological deficits (DINDs) and new cerebral infarction (NCI). We systematically searched PubMed, Embase, Cochrane library and Medline from inception until October, 2015.