Design, synthesis and antitumor activity of a novel FGFR2-selective degrader to overcome resistance of the FGFR2V564F 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. In this study, we designed several PROTACs with different E3 ligands based on LY2874455. By screening the length of the linker and the binding site in various degraders, we obtained a novel and highly efficient FGFR2-selective degrader 28e (DC50 = 0.645 nM, DCmax = 86 %). Compound 28e selectively degraded FGFR2 and essentially avoided degradation of FGFR1,3,4 isoforms (DC50 > 300 nM). Compound 28e significantly inhibited the proliferation of FGFR2-overexpressing cell lines, including KATOIII, SNU16, and AN3CA (IC50 = 0.794 nM/0.207 nM/4.626 nM), comparable to parental inhibitors. At the same time, the preferred compound showed superiority over the parental inhibitor in kinase inhibitory activity against the gatekeeper mutant isoform FGFR2V564F (IC50 = 0.121 nM). In summary, we identified 28e as a novel selective degrader of FGFR2 with high potency and high potential to overcome resistance to gatekeeper mutation. The discovery of 28e provides new evidence for the strategy of pan-inhibitor-based development of selective degrading agents.

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.Importantly, SKLB-0124 induced proteasome dependent degradation of PRMT6 and significantly inhibited the proliferation of HCC827 and MDA-MB-435 cells. Moreover, SKLB-0124 effectively induced apoptosis and cell cycle arrest in these two cell lines. Our data clarified that SKLB-0124 is a promising selective PRMT6 degrader for cancer therapy which is worthy of further evaluation.

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. METHODS: In this retrospective study, 84 consecutive decompressions with duraplasty were analyzed. Two types of grafts (nonautologous [Non-Auto G], 90.5% and autologous [Auto G], 9.5%) and 2 graft fixations (suturing [S], 31.0%; and suturing plus gluing [S + G], 69.0%) were used in 3 different combinations: Non-Auto G S: 31.0%; Non-Auto G S + G: 59.5%, and Auto G S + G: 9.5%. All patients were followed up for 3 months. Clinical results were evaluated using the Gestalt scale, and syringomyelia results were evaluated using magnetic resonance imaging. RESULTS: According to the Gestalt scale, 82.1% of the patients showed improvement 3 months post operation, and the improvement was not related to the type of graft (P = 0.90), fixation (P = 0.90), or duraplasty (P = 0.81). Decreased syringomyelia was observed in 76.4% of the patients. It was not associated with the graft (P = 0.53), fixation (P = 0.72), or duraplasty (P = 0.80). Meningitis occurred in the Auto G S + G, Non-Auto G S + G and Non-Auto G S groups (25%, 48%, and 23.1%, respectively; P = 0.30), and their formations were not related to the k graft type (P = 0.57) or fixation (P = 0.19). CONCLUSIONS: Autologous and nonautologous dural grafts can be performed using either sutures or sutures plus glue, as both result in similar outcomes.

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. All randomized controlled trials related to the functions of clazosentan in aSAH were included. Analyses were performed following the method guideline of Cochrane Back Review Group. Four randomized placebo-controlled trials met eligibility criteria and enrolled a total of 2159 patients. The meta-analysis demonstrated a significant decrease in the incidence of DINDs (relative risk, 0.49 and 95% CI, 0.33-0.73) and NCI (relative risk, 0.42 and 95% CI, 0.25-0.71) in patients treated with a high dose of clazosentan (15 mg/h) after aSAH. In addition, a high dose of clazosentan (15 mg/h) had no more effect on the incidence of adverse events than that of a low dose (1-5 mg/h). The results of the present meta-analysis show that a high dose of clazosentan significantly reduced the incidence of the vasospasm-related DINDs and NCI. Further study is required to fully understand the potential usefulness of clazosentan in patients with aSAH.