Abstract
Cancer immunotherapy has been revolutionized by the development of monoclonal antibodies (mAbs) that inhibit interactions between immune checkpoint molecules, such as programmed cell-death 1 (PD-1), and its ligand PD-L1. However, mAb-based drugs have some drawbacks, including poor tumor penetration and high production costs, which could potentially be overcome by small molecule drugs. BMS-8, one of the potent small molecule drugs, induces homodimerization of PD-L1, thereby inhibiting its binding to PD-1. Our assay system revealed that BMS-8 inhibited the PD-1/PD-L1 interaction with IC50 of 7.2 μM. To improve the IC50 value, we designed and synthesized a small molecule based on the molecular structure of BMS-8 by in silico simulation. As a result, we successfully prepared a biphenyl-conjugated bromotyrosine (X) with IC50 of 1.5 μM, which was about five times improved from BMS-8. We further prepared amino acid conjugates of X (amino-X), to elucidate a correlation between the docking modes of the amino-Xs and IC50 values. The results suggested that the displacement of amino-Xs from the BMS-8 in the pocket of PD-L1 homodimer correlated with IC50 values. This observation provides us a further insight how to derivatize X for better inhibitory effect.
Highlights
Immunotherapy has recently emerged as a fourth modality for cancer therapy, together with surgery, chemotherapy, and radiation therapy [1,2,3,4]
One of the major immune checkpoint pathways is inactivated by the binding of programmed cell-death 1 (PD-1) [7], which is largely expressed on T cells, and its ligand PD-L1 [3,8,9], which is mainly expressed on antigen-presenting cells under physiological conditions but is upregulated on cancer cells [10]
This study reports that we prepared the new biphenyl-conjugated bromotyrosine, which inhibits the PD-1/PD-L1 interaction with better effect than that of BMS-8
Summary
Immunotherapy has recently emerged as a fourth modality for cancer therapy, together with surgery, chemotherapy, and radiation therapy [1,2,3,4]. One of the major immune checkpoint pathways is inactivated by the binding of programmed cell-death 1 (PD-1) [7], which is largely expressed on T cells, and its ligand PD-L1 [3,8,9], which is mainly expressed on antigen-presenting cells under physiological conditions but is upregulated on cancer cells [10]. PD-L1 binding to PD-1 suppresses T-cell function, including cytolytic activity, leading to downregulation of the anti-tumor immune response [2,5]. (CD80, CD86) on activated antigen-presenting cells or cancer cells to cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) on T cells, which suppresses T-cell activity [11,12] Identification of these immunosuppressive pathways led to the development of monoclonal antibody (mAb)-based. 3-brobmroomtyortoysrionsein(e2X) wwearsesysnetlhecetseizdedasafftreargcmonejungteadtiosntroufc1tuanreds2..AWbe icpohnejungyalt-ecdoanjvuagriaetteydofbarmominootaycriodssine X was saysnatdhdeistiioznesd, taofttheer acmoninjuo-gaantidocnarobfo1xyaln-gdro2u.pWs oef Xcotonjruegveaatlemd oalevcaurlaiertmyeocfhaanmisimnoofatchiedsinahsibaitdiodni.tions, to the amino- and carboxyl-groups of X to reveal molecular mechanism of the inhibition
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