近日，贝达药业公开小分子PD-(L)1抑制剂专利——《免疫调节剂及其组合物和制备方法》（CN319954329），同样最早申请日可追溯到2019.1.31，此前本站也报道过东阳光小分子抑制剂专利情况，本专利最早是2018.3申请，本发明涉及用作PD-L1和PD-1相互作用的抑制剂的化合物。PD-1和PD-L1相互作用的抑制剂可以用于治疗癌症和其他感染病。
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贝达药业PD-L1抑制剂BPI-371153临床申请于2021年11月12日；
2022年1月17日，贝达药业公布获得临床默示许可。
AACR22公布数据如下：
BPI-371153 demonstrates high binding affinity to human PD-L1, induces PD-L1 dimeralization and disrupts PD-L1:PD-1 interaction (IC50 <1 nM by HTRF assay). BPI-371153 induces PD-L1 internalization with an IC50 value of 4.2 nM as detected by flow cytometry, activates nuclear factor of activated T cell (NFAT) signaling in cell-based reporter assay, and effectively stimulates IFN-γ release in human peripheral blood monocyte-mediated tumor cell killing assay. In a syngeneic mouse model with murine MC38 colon tumor cells expressing human PD-L1 (MC38-hPD-L1 model), BPI-371153 suppressed tumor growth to an extent comparable to an anti-PD-L1 antibody. In immunocompromised mice grafted with the same cell line, no growth inhibition was observed, confirming that the pharmacologic effect of BPI-371153 indeed came from the immune system. In addition, this compound exhibits favorable ADME properties, with high oral exposure across multiple pre-clinical species. Phase I clinical trial of BPI-371153 is planned for early 2022.
| 通式、实施例及对照结构式 |
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因此仍然强烈需要针对PD-1和PD-L1蛋白/蛋白相互作用的更有效更易于施用的治疗药物。在本发明中，申请人发现了一种有效的小分子可以作为PD-L1与PD-1的相互作用的抑制剂，因此可用于治疗性给药以增强针对癌症和/or传染病的免疫力。这些小分子有望成为具有良好稳定性，溶解性，生物利用度，治疗指数和毒性值的药物，这对于成为促进人类健康的有效药物至关重要。
Recently, small molecules have been described to binding to PD-L1 in WO2015033299（Aurigene Discovery）, WO2015033301（Aurigene Discovery）, WO2015034820（Bristol-Myers Squibb）, WO2018183171（Bristol-Myers Squibb）, WO2018119224（Incyte）, WO2018119266（Incyte）, etc. Moreover, small molecule inhibitors that directly target PD-1 or PD-L1 are still not approved.
Accordingly, there is still great demand for more potent, and more easily administered therapeutics against PD-1/PD-L1 protein/protein interactions. In this invention, applicant discovered potent small molecules that can have activity as inhibitors of the interaction of PD-L1 with PD-1, and thus may be useful for therapeutic administration to enhance immunity against cancer and/or infectious diseases. These small molecules are expected to be useful as pharmaceuticals with desirable stability, solubility, bioavailability, therapeutic index and toxicity values that are crucial to become efficient medicines to promote human health.
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