Inhibitors of the PD-1/PD-L1 Pathway Can Mobilize the Immune System: An Innovative Potential Therapy for Cancer and Chronic Infections

Ahmed F Abdel-Magid

doi:10.1021/acsmedchemlett.5b00148

editorial

. 2015 Apr 14;6(5):489–490. doi: 10.1021/acsmedchemlett.5b00148

Inhibitors of the PD-1/PD-L1 Pathway Can Mobilize the Immune System: An Innovative Potential Therapy for Cancer and Chronic Infections

Ahmed F Abdel-Magid ^1,^*

PMCID: PMC4434459 PMID: 26005519

Title:	Compounds Useful as Immunomodulators
Patent Application Number:	WO 2015/034820 Al	Publication date:	12 March 2015
Priority Application:	US 61/873,398	Priority date:	4 September 2013
Inventors:	Chupak, L. S.; Zheng, X.
Assignee Company:	Bristol-Myers Squibb Company; Route 206 and Province Line Road, Princeton, NJ 08543, USA
Disease Area:	Cancer and infectious diseases such as hepatitis C	Biological Target:	PD-1/PD-L1 pathway
Summary:	The invention in this patent application relates to compounds represented generally by formula (I), which possess activities as inhibitors of the PD-1/PD-L1 interactions and therefore may potentially be useful in the treatment of cancer as well as infectious diseases such as hepatitis C.
	T-cells or lymphocytes are white blood cells that are essential for the immune system. They are capable of searching for and destroying infected and/or cancerous cells. Programmed death protein 1 (PD-1), also known as cluster of differentiation 279 (CD279), is a cell surface receptor on the T cells. The binding of PD-1 with either one of its two known ligands, programmed death-ligands 1 and 2 (PD-Ll or PD-L2), has been shown to suppress T cell receptor activating signals. The PD-l/PD-L1 pathway down regulates the immune responses during resolution of an infection or a tumor, or during the development of self-tolerance.
	Studies have shown that blocking the PD-1/PD-Ll interactions using antibodies to the PD-Ll protein restores and augments T cell activation in many systems. A recent study has shown that therapy with a monoclonal antibody to PD-Ll benefited patients with advanced cancer. Blocking the PD-1/PD-Ll pathway by monoclonal antibodies enhanced the immune response and resulted in tumor rejection or control of infection in preclinical animal models. It can also restore in vitro antigen-specific functionality to T cells from HIV, HCV, or HBV patients. Other reports show that blocking the PD-1/PD-L1 interaction enhances T cell activity in chronic infection systems and may augment therapeutic immune response to a number of histologically distinct tumors. It also enhances the responses to vaccination, including therapeutic vaccination in chronic infections.
	The term “T cell exhaustion” describes the conditions of the T cells resulting from chronic antigen stimulation that occurs during chronic infections and tumor disease. These cells are characterized by elevated levels of PD-1 and dysfunctional activities toward chronic antigen. Targeting PD-L1 protein to inhibit the PD-1/PD-L1 pathway has been shown to restore antigen-specific T cell immune functions in vitro and in vivo, including enhanced responses to vaccination in the setting of tumor or chronic infection.
	The inhibition of the interaction of PD-Ll with PD-1 is thus a viable and promising therapeutic target for the treatment of cancer and/or chronic infections. The invention in this patent application presents compounds with activities as inhibitors of the PD-1/PD-Ll protein/protein interactions. These compounds may potentially be useful therapy to enhance immunity in patients with cancer or chronic infections.
Important Compound Classes:
Key Structures:	The inventors listed the structures of 297 examples of formula (I) including the following six representative examples:
Biological Assay:	• Homogenous Time-Resolved Fluorescence (HTRF) binding assay
Biological Data:	The inventors listed the IC₅₀ data from the HTRF binding assay for the 297 examples of formula (I). The following table contains the assay data for the above six representative examples:
	Codes for IC₅₀ values: A = 0.006–0.10 μM; B = 0.11–1.00 μM; C = 1.01–10 μM
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