Department of Chemistry, Bristol-Myers Squibb Company, P.O. Box 4000, Princeton, NJ, USA.
BBRC, Special Economic Zone, Biocon Park, Jigani Link Road, Bangalore, India.
Bioorg Med Chem. 2018 Mar 1;26(5):1026-1034. doi: 10.1016/j.bmc.2018.01.014. Epub 2018 Jan 31.
The TGFβ-TGFβR signaling pathway has been reported to play a protective role in the later stages of tumorigenesis via increasing immunosuppressive Treg cells and facilitating the epithelial to mesenchymal transition (EMT). Therefore, inhibition of TGFβR has the potential to enhance antitumor immunity. Herein we disclose the identification and optimization of novel heterobicyclic inhibitors of TGFβRI that demonstrate potent inhibition of SMAD phosphorylation. Application of structure-based drug design to the novel pyrrolotriazine chemotype resulted in improved binding affinity (Ki apparent = 0.14 nM), long residence time (T > 120 min) and significantly improved potency in the PSMAD cellular assay (IC = 24 nM). Several analogs inhibited phosphorylation of SMAD both in vitro and in vivo. Additionally, inhibition of TGFβ-stimulated phospho-SMAD was observed in primary human T cells.
TGFβ-TGFβR 信号通路已被报道在肿瘤发生的后期通过增加免疫抑制性 Treg 细胞和促进上皮间质转化（EMT）来发挥保护作用。因此，抑制 TGFβR 有可能增强抗肿瘤免疫。在此，我们揭示了新型异双环 TGFβRI 抑制剂的鉴定和优化，这些抑制剂对 SMAD 磷酸化具有很强的抑制作用。基于结构的药物设计在新型吡咯并三嗪化学型中的应用，提高了结合亲和力（Ki 表观 = 0.14 nM）、延长了停留时间（T > 120 min），并显著提高了 PSMAD 细胞测定中的效力（IC = 24 nM）。几种类似物在体外和体内均抑制了 SMAD 的磷酸化。此外，在原代人 T 细胞中观察到 TGFβ 刺激的磷酸化 SMAD 抑制。
