RESUMO
Blockade of the programmed cell death 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) interaction has emerged as a powerful strategy in cancer immunotherapy. Recently, there have been enormous efforts to develop potent PD-1/PD-L1 inhibitors. In particular, Bristol-Myers Squibb (BMS) and Aurigene Discovery Technologies have individually disclosed several promising PD-1/PD-L1 inhibitors, whose detailed experimental data are not publicly disclosed. In this work, we report the rigorous and systematic in vitro characterization of a selected set of potent PD-1/PD-L1 macrocyclic peptide (BMSpep-57) and small-molecule inhibitors (BMS-103, BMS-142) from BMS and a peptidomimetic small-molecule inhibitor from Aurigene (Aurigene-1) using a series of biochemical and cell-based assays. Our results confirm that BMS-103 and BMS-142 are strongly active in biochemical assays; however, their acute cytotoxicity greatly compromised their immunological activity. On the other hand, Aurigene-1 did not show any activity in both biochemical and immunological assays. Furthermore, we also report the discovery of a small-molecule immune modulator, whose mode-of-action is not clear; however, it exhibits favorable drug-like properties and strong immunological activity. We hope that the results presented here will be useful in guiding the development of next-generation PD-1/PD-L1 small molecule inhibitors.
Assuntos
Antígeno B7-H1/metabolismo , Bibliotecas de Moléculas Pequenas/metabolismo , Anticorpos Monoclonais/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/química , Antígeno B7-H1/genética , Sítios de Ligação , Sobrevivência Celular/efeitos dos fármacos , Genes Reporter , Humanos , Imunoensaio , Interleucina-2/metabolismo , Células Jurkat , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Simulação de Dinâmica Molecular , Peptidomiméticos , Ligação Proteica , Estrutura Terciária de Proteína , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologiaRESUMO
Formation and rearrangement of several oxonium ylides containing cyclopropylcarbinyl migrating groups were studied. Efficient ring-contraction by [1,2]-shift to form cyclopropane-substituted cyclobutanones was observed, with no competing cyclopropane fragmentation. Substitution with the hypersensitive mechanistic probe (trans,trans-2-methoxy-3-phenylcyclopropyl)methyl led to cyclopropane fragmentation via an apparent heterolytic pathway, providing the first evidence for ion pair intermediates from ylide cleavage, and suggesting a possible alternative heterolytic mechanism for the Stevens [1,2]-shift.
