Design, synthesis, and evaluation of PD-1/PD-L1 small-molecule inhibitors bearing a rigid indane scaffold

Discovery of Highly Potent Small-Molecule PD-1/PD-L1 Inhibitors with a Novel Scaffold for Cancer Immunotherapy

“…Lastly, LD 231 represents the absorption value of LDH detected in MDA-MB-231 cells that were not treated with PBMCs or compound X14 but were fully lysed by the lysis buffer at the end of the culture. 18 Pharmacokinetic Study. All animal experiments mentioned in this research were approved by the Institutional Animal Care and Use Committee of China Pharmaceutical University (SYXK2018-0019) and carried out by the institutional guidelines for the care and use of laboratory animals.…”

“…This mechanism helps prevent the organism from producing an excessive immune response and maintain the immune system’s homeostasis. ,− In most of the tumor cells, PD-L1 is overexpressed, leading to the inhibition of T-cell proliferation and their ability to kill tumor cells. This is achieved through the interaction between PD-L1 on tumor cells and PD-1 on the surface of T cells, allowing the tumor to evade immune surveillance. ,, Several monoclonal antibodies (mAbs) (e.g., nivolumab, pembrolizumab, avelumab, and atezolizumab) targeting PD-1/PD-L1 have been approved by the U.S. Food and Drug Administration (FDA) for treating different types of tumors. , However, these mAbs have certain inherent drawbacks that restrict their wider use in clinical settings. These limitations include high production costs, poor permeability in tissues and tumors, lack of oral bioavailability, and the occurrence of immune-related adverse events (irAEs). , In comparison, small-molecule compounds exhibit lower immunogenicity, higher stability, better organ or tumor penetration, and lower production costs.…”

“…10,15,16 Several monoclonal antibodies (mAbs) (e.g., nivolumab, pembrolizumab, avelumab, and atezolizumab) targeting PD-1/PD-L1 have been approved by the U.S. Food and Drug Administration (FDA) for treating different types of tumors. 17,18 However, these mAbs have certain inherent drawbacks that restrict their wider use in clinical settings. These limitations include high production costs, poor permeability in tissues and tumors, lack of oral bioavailability, and the occurrence of immune-related adverse events (irAEs).…”

“…Qin and co-workers reported a series of compounds that modified the benzyl ether and methoxypyridine moiety of BMS-202 . Among them, compound 4 ( N11 ) demonstrated a potent inhibitory activity on PD-1/PD-L1 interaction (IC 50 = 6.3 nM). , Jiang’s group reported multiple compounds targeting PD-1/PD-L1 interaction in several articles, with compound 5 ( D3 ) being identified as the most potent compound (IC 50 = 2.2 nM). ,, Several highly active compounds were successfully obtained by Yang’s group through cyclizing the benzyl ether moiety, using the structures of BMS-202 and BMS-1001 as a basis. Among them, compound 6 ( S4-1 ) exhibited significant in vivo antitumor activity when intraperitoneally injected at a dosage of 25 mg/kg in a humanized MC38 mouse model of colorectal cancer .…”

Discovery of Novel PD-L1 Inhibitors That Induce the Dimerization, Internalization, and Degradation of PD-L1 Based on the Fragment Coupling Strategy

“…Our group has been committed to the discovery of small-molecule PD-L1 inhibitors and has reported various potent PD-L1 inhibitors with great PD-1/PD-L1 inhibitory activity and in vivo antitumor immunity (Figure , 4 – 7 ). − Herein, we report our discovery of novel small-molecule PD-L1 inhibitors that the promote dimerization, internalization, and degradation of PD-L1. By analyzing of the X-ray structure of the 4 /PD-L1 complex (Figure A), 29 PD-L1 inhibitors containing biphenyl core skeleton are designed and synthesized based on the fragment coupling strategy.…”