Macrocyclic Compounds from Ansamycin Antibiotic Class as Inhibitors of PD1–PDL1 Protein–Protein Interaction

Patil, Sachin; Yoon, Suk-Chung; Aradhya, Abhay; Hofer, Jeremy; Fink, Madison A.; Enley, Erika S.; Fisher, James E.; Herb, Marie C.; Klingos, Anthony; Proulx, James T.; Fedorky, Megan T.

doi:10.1248/cpb.c17-00800

Cited by 17 publications

(10 citation statements)

References 23 publications

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“…This may provide an alternative scaffold and extra fragments for the design of new small-molecule antagonists of the PD-1/PD-L1 pathway [38,39,44] (See also Section 2.2, Figure 17). For example, an interesting application of the MCPs as potential inhibitors of PD-L1 was proposed by Patil et al [45] who showed that macrocyclic compounds 5 and 6 from the ansamycin class of antibiotics are capable to inhibit the PD-1/PD-L1 interaction (Figure 4).…”

Section: Inhibitors Of the Pd-1/pd-l1 Interactionmentioning

confidence: 99%

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Development of the Inhibitors That Target the PD-1/PD-L1 Interaction—A Brief Look at Progress on Small Molecules, Peptides and Macrocycles

et al. 2019

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Cancer immunotherapy based on antibodies targeting the immune checkpoint PD-1/PD-L1 pathway has seen unprecedented clinical responses and constitutes the new paradigm in cancer therapy. The antibody-based immunotherapies have several limitations such as high production cost of the antibodies or their long half-life. Small-molecule inhibitors of the PD-1/PD-L1 interaction have been highly anticipated as a promising alternative or complementary therapeutic to the monoclonal antibodies (mAbs). Currently, the field of developing anti-PD-1/PD-L1 small-molecule inhibitors is intensively explored. In this paper, we review anti-PD-1/PD-L1 small-molecule and peptide-based inhibitors and discuss recent structural and preclinical/clinical aspects of their development. Discovery of the therapeutics based on small-molecule inhibitors of the PD-1/PD-L1 interaction represents a promising but challenging perspective in cancer treatment.

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Section: Inhibitors Of the Pd-1/pd-l1 Interactionmentioning

confidence: 99%

“…A particularly good result was obtained for 6 that showed an IC 50 of approximately 25 µM. This led the authors to conclude that such macrocycles could become an inspiration for the development and optimization of a potent and truly small-molecule antagonist of the PD-1/PD-L1 interaction [45].…”

Section: Inhibitors Of the Pd-1/pd-l1 Interactionmentioning

confidence: 99%

Development of the Inhibitors That Target the PD-1/PD-L1 Interaction—A Brief Look at Progress on Small Molecules, Peptides and Macrocycles

et al. 2019

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“…Recently, Zak et al revealed the molecular features of the human PD-1/PD-L1 interaction based on the X-ray structure of the complex, and several hot spots located on the PD-L1 molecule were shown to be involved in the formation of the complex (15,30). To date, several small molecules, macrocyclic peptides and peptide mimetics targeting the PD-1/PD-L1 interaction have been reported (8,18,19), primarily in patent applications, but almost no fully validated and qualified therapeutics exist. Recently, the binding action and biological activities of potent small molecule inhibitors of PD-1/PD-L1 have been reported by Bristol-Myers Squibb (BMS) (1,31,32).…”

Section: Development Of Humanized Nog-dko Mice Six-mentioning

confidence: 99%

Antitumor activity of the PD-1/PD-L1 binding inhibitor BMS-202 in the humanized MHC-double knockout NOG mouse

et al. 2019

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Recently, the first series of small molecule inhibitors of PD-1/PD-L1 were reported by Bristol-Myers Squibb (BMS), which were developed using a homogeneous time-resolved fluorescence (HTRF)-based screening investigation of the PD-1/PD-L1 interaction. Additional crystallographic and biophysical studies showed that these compounds inhibited the interaction of PD-1/PD-L1 by inducing the dimerization of PD-L1, in which each dimer binds one molecule of the stabilizer at its interface. However, the immunological mechanism of the antitumor effect of these compounds remains to be elucidated. In the present study, we focused on BMS-202 (a representative of the BMS compounds) and investigated its antitumor activity using in vitro and in vivo experiments. BMS-202 inhibited the proliferation of strongly PD-L1-positive SCC-3 cells (IC 50 15 μM) and anti-CD3 antibody-activated Jurkat cells (IC 50 10 μM) in vitro. Additionally, BMS-202 had no regulatory effect on the PD-1 or PD-L1 expression level on the cell surface of these cells. In an in vivo study using humanized MHC-double knockout (dKO) NOG mice, BMS-202 showed a clear antitumor effect compared with the controls; however, a direct cytotoxic effect was revealed to be involved in the antitumor mechanism, as there was no lymphocyte accumulation in the tumor site. These results suggest that the antitumor effect of BMS-202 might be partly mediated by a direct off-target cytotoxic effect in addition to the immune response-based mechanism. Also, the humanized dKO NOG mouse model used in this study was shown to be a useful tool for the screening of small molecule inhibitors of PD-1/PD-L1 binding that can inhibit tumor growth via an immune-response-mediated mechanism.

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“…[7] As a result, different alternative therapeutics that are much smaller than these mAbs are currently being explored to target the binding interfaces on both the PD-1 and PD-L1 receptors. These include small PD-1 protein fragments [8] and macrocyclic peptides, [9,10] many of which showed significantly better activity than the larger mAbs. These peptides and peptidomimetics thus can provide a good starting point in designing and optimizing the potent, truly small-molecule antagonists of the PD-1/PD-L1 interaction.…”

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Identification of the FDA‐Approved Drug Pyrvinium as a Small‐Molecule Inhibitor of the PD‐1/PD‐L1 Interaction

et al. 2021

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Immune checkpoint blockade involving inhibition of the PD‐1/PD‐L1 interaction has provided unprecedented clinical benefits in treating a variety of tumors. To date, a total of six antibodies that bind to either PD‐1 or PD‐L1 protein and in turn inhibit the PD‐1/PD‐L1 interaction have received clinical approvals. Despite being highly effective, these expensive large biotherapeutics possess several inherent pharmacokinetic limitations that can be successfully overcome through the use of low‐molecular‐weight inhibitors. One such promising approach involves small‐molecule induced dimerization and sequestration of PD‐L1, leading to effective PD‐1/PD‐L1 inhibition. Herein, we present the discovery of such potential bioactive PD‐L1 dimerizers through a structure‐ and ligand‐based screening of a focused library of approved and investigational drugs worldwide. Pyrvinium, an FDA‐approved anthelmintic drug, showed the highest activity in our study with IC50 value of ∼29.66 μM. It is noteworthy that Pyrvinium, being an approved drug, may prove especially suitable as a good starting point for further medicinal chemistry efforts, leading to design and development of even more potent structural analogs as selective PD‐1/PD‐L1 inhibitors. Furthermore, the adopted integrated virtual screening protocol may prove useful in screening other larger databases of lead‐ and drug‐like molecules for hit identification in the domain of small‐molecule PD‐1/PD‐L1 inhibitors.

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Macrocyclic Compounds from Ansamycin Antibiotic Class as Inhibitors of PD1–PDL1 Protein–Protein Interaction

Cited by 17 publications

References 23 publications

Development of the Inhibitors That Target the PD-1/PD-L1 Interaction—A Brief Look at Progress on Small Molecules, Peptides and Macrocycles

Development of the Inhibitors That Target the PD-1/PD-L1 Interaction—A Brief Look at Progress on Small Molecules, Peptides and Macrocycles

Antitumor activity of the PD-1/PD-L1 binding inhibitor BMS-202 in the humanized MHC-double knockout NOG mouse

Identification of the FDA‐Approved Drug Pyrvinium as a Small‐Molecule Inhibitor of the PD‐1/PD‐L1 Interaction

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