(±)-13e(Chinese Academy of Medical Sciences and Peking Union Medical College)

FMS-like tyrosine kinase 3 (FLT3) is a validated therapeutic target in acute myeloid leukemia (AML). However, numerous single-agent FLT3 or multitarget inhibitors fail to achieve complete and sustained suppression of FLT3 signaling due to the development of drug resistance. Herein, we report the design, synthesis, and evaluation of a novel series of dual BET-kinase degraders targeting FLT3, JAK2, and BRD4. Optimization led to 13e, which efficiently degraded FLT3, JAK2, and BRD4 in MV4;11 cells with DC₅₀ values of 5.23, 0.678, and 1.17 nM, respectively. Mechanistic studies confirmed cereblon- and proteasome-dependent degradation. 13e significantly inhibited MV4;11 cell proliferation and demonstrated promising antitumor activity in an MV4;11 xenograft model. Additionally, 13e showed enhanced antiproliferative activity against FLT3 mutant-transformed Ba/F3 cells, indicating its potential to overcome resistance. Collectively, 13e represents a highly promising FLT3/JAK2/BRD4 degrader with potent antileukemic activity and the ability to overcome resistance associated with current FLT3 inhibitors.

Due to the prolonged misuse of antimicrobial agents and the development of various resistance mechanisms, Methicillin-resistant Staphylococcus aureus (MRSA) has emerged as a leading threat to the public health. The production of a penicillin binding protein 2a (PBP2a) plays a crucial role in cell wall synthesis of MRSA, and conformational alterations in PBP2a impede the effective binding of β-lactam antibiotics, the most effective class of antibiotic, to the active site. The PBP2a allosteric site located 60 Å from the active site, and binding of allosteric site significantly influences the conformational dynamics of the active site. Based on the effect of nucleoside which re-sensitizes MRSA to β-lactam antibiotics, we conducted extensive virtual screening to design and synthesize a series of novel nucleoside inhibitors targeting the allosteric site of MRSA PBP2a. These inhibitors exhibit a distinct chemical structure compared to existing clinical antibiotics. Notably, compound 13e demonstrated a minimum inhibitory concentration (MIC) of 16 µg/mL against MRSA strain, showcasing superior antibacterial activity relative to the reference antibiotic. Time-kill curve indicated that compound 13e effectively inhibit bacterial growth. Interestingly, a synergistic effect was observed at low concentrations of compound 13e in combination treatment with Oxacillin, whereas antagonism occurred at higher concentrations of compound 13e. The morphological observation showed the integrity of the bacterial cell wall was disrupted after compound 13e treatment, and it exhibited a lower propensity for developing resistance compared to cephalosporin. Additionally, this compound did not affect the viability of normal human intestinal epithelial cells (HIEC) and brain microvascular endothelial cells at concentration much higher than MIC. Over all, this unique antibacterial mechanism underscores the optimization potential of these nucleoside compounds, providing new perspectives and methodologies for the development of novel antimicrobial agents.