Targeting FAK/PYK2 with SJP1602 for Anti-Tumor Activity in Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) presents significant challenges due to its aggressive nature and limited treatment options. Focal adhesion kinase (FAK) has emerged as a critical factor promoting tumor growth and metastasis in TNBC. Despite encouraging results from preclinical and early clinical trials with various FAK inhibitors, none have yet achieved clinical success in TNBC treatment. This study investigates the therapeutic potential of a novel dual inhibitor of FAK and PYK2, named SJP1602, for TNBC. In vitro experiments demonstrate that SJP1602 effectively inhibits FAK and PYK2 activities, showing potent effects on both kinases. SJP1602 shows concentration-dependent inhibition of cell growth, migration, invasion, and 3D spheroid formation in TNBC cell lines, surpassing the efficacy of other FAK inhibitors. Pharmacokinetic studies in rats indicate favorable bioavailability and sustained plasma concentrations of SJP1602, supporting its potential as a therapeutic agent. Furthermore, in TNBC xenograft models, SJP1602 exhibits significant dose-dependent inhibition of tumor growth. These promising results emphasize the potential of SJP1602 as a potent dual inhibitor of FAK and PYK2, deserving further investigation in clinical trials for TNBC treatment

Identification of Optically Active Pyrimidine Derivatives as Selective 5-HT2C Modulators

A series of pyrimidine derivatives 4a–i were synthesized and evaluated for their binding affinities towards 5-HT2C receptors. With regard to designed molecules 4a–i, the influence of the size of alkyl ether and the absolute configuration of a stereogenic center on the 5-HT2C binding affinity and selectivity was studied. The most promising diasteromeric mixtures 4d and 4e were selected in the initial radioligand binding assay and they were further synthesized as optically active forms starting from optically active alcohols 5d and 5e, prepared by an enzymatic kinetic resolution. Pyrimidine analogue (R,R)-4e displayed an excellent 5-HT2C binding affinity with good selectivity values against a broad range of other 5-HT receptor subtypes

Construction of 8‑Azabicyclo[3.2.1]octanes via Sequential DDQ-Mediated Oxidative Mannich Reactions of <i>N</i>‑Aryl Pyrrolidines

A concise synthesis of 8-azabicyclo­[3.2.1]­octanes via sequential oxidative Mannich reactions is described. This approach involves an intermolecular oxidative Mannich coupling reaction between <i>N</i>-aryl pyrrolidines with TMS enol ether and a subsequent intramolecular oxidative Mannich cyclization of the corresponding silyl enol ether. DDQ is used as a key oxidant for both reactions