Combination Therapy Comprising A2A/A2B and PD-1/PD-L1 Inhibitors for Treating Cancer

Important Compound Classes

Title

Combination Therapy Comprising A2A/A2B and PD-1/PD-L1 Inhibitors

Patent Publication Number

WO 2021/138512 A1

Publication Date

July 8, 2021

Priority Application

US 62/956,960

Priority Date

January 3, 2020

Inventors

Wang, H.; Carlsen, P. N.; Huang, T.; Li, Y.; Lin, L.; Qi, C.; Thekkat, P. U.; Wang, X.; Wu, L.; Yao, W.; Zhu, W.

Assignee Company

Incyte Corporation, USA

Disease Area

Cancer

Biological Target

A2A/A2B and PD-1/PD-L1

Summary

Adenosine is an extracellular signaling molecule that can modulate immune responses through many immune cell types. Adenosine plays a vital role in various physiological functions. It is involved in the synthesis of nucleic acids when linked to three phosphate groups. It forms ATP, the integral component of the cellular energy system.

There are four known subtypes of adenosine receptor in humans, including A1, A2A (ADORA2A), A2B (ADORA2B), and A3 receptors. A2A receptors are mostly expressed on lymphoid-derived cells, including T-effector cells, T-regulatory cells, and natural killer cells. Blocking the A2A receptor can prevent downstream immunosuppressive signals that temporarily inactivate T-cells. A2B receptors are mainly expressed on monocyte-derived cells including dendritic cells, tumor-associated macrophages, myeloid-derived suppressive cells (MDSCs), and mesenchymal stromal/stem cells (MSCs). Blocking A2B receptor in preclinical models can suppress tumor growth, block metastasis, and increase the presentation of tumor antigens.

The immune system plays an important role in controlling and eradicating diseases such as cancer. Programmed Death-1 (PD-1) is expressed on activated T-cells, B-cells, and monocytes. PD-1 has two ligands, PD-L1 and PD-L2, and they differ in their expression patterns. PD-L1 is highly expressed on almost all tumor cells. In fact, tumor PD-L1 expression status has been shown to be prognostic in multiple tumor types. Development of a therapeutic approach to block PD-1/PD-L1 protein–protein interaction and thereby treating cancer appears to be a promising approach.

The present application describes a combination therapy comprising A2A/A2B and PD-1/PD-L1 inhibitors for the treatment of cancer. The A2A/A2B inhibitors include novel compounds of Formula (I), or Formula (II), and Formula (III). The PD-1/PD-L1 inhibitors include pembrolizumab, nivolumab, atezolizumab, and ANTIBODY X. Further, the application discloses compounds, their preparation, use, pharmaceutical composition, and treatment.

Definitions

C_y1 = phenyl which is substituted by 1 or 2 substituents selected from halo and CN;

C_y2 = 5–6-membered heteroaryl or 4–7-membered heterocycloalkyl, wherein the 5–6-membered heteroaryl or 4–7-membered heterocycloalkyl of C_y2 are each optionally substituted with 1, 2, or 3 groups each independently selected from C_1–3 alkyl, C_1–3 alkoxy, NH₂, NH(C_1–3 alkyl), and N(C_1–3 alkyl);

R₂ = phenyl-C_1–3 alkyl-, C_3–7 cycloalkyl-C_1–3 alkyl-, (5–7-membered heteroaryl)-C_1–3 alkyl-, (4–7-membered heterocycloalkyl)-C_1–3 alkyl-, and OR_a2, wherein the phenyl-C_1–3 alkyl-, C_3–7 cycloalkyl-C_1–3 alkyl-, (5–7-membered heteroaryl)-C_1–3 alkyl-, (4–7-membered heterocycloalkyl)-C_1–3 alkyl- of R₂ are each optionally substituted with 1, 2, or 3 selected R_c substituents; and

R₄ = phenyl-C_1–3 alkyl-, C_3–7 cycloalkyl-C_1–3 alkyl-, (5–6-membered heteroaryl)-C_1–3 alkyl-, and (4–7-membered heterocycloalkyl)-C_1–3 alkyl-, wherein phenyl-C_1–3 alkyl-, C_3–7 cycloalkyl-C_1–3 alkyl-, (5–6-membered heteroaryl)-C_1–3 alkyl-, and (4–7-membered heterocycloalkyl)-C_1–3 alkyl- of R₄ are each optionally substituted with 1, 2, or 3 selected R_4A substituents.

Key Structures

Biological Assay

The A2A Tag-lite HTRF assay and adenosine A2B receptor cyclic AMP GS assay were performed. The compounds described in this application were tested for their ability to inhibit A2A/A2B. The A2A K_i (nM) and A2B cAMP EC₅₀ (nM) are shown in the following table.

Biological Data

The table below shows representative compounds were tested for A2A/A2B inhibition. The biological data obtained from testing representative examples are listed in the following table.

For A2A K_i and A2B cAMP EC₅₀: “*” means ≤10 nM; “**” means >10 nM to ≤100 nM; “***” means >100 nM to ≤1 μM; “****” means >1 μM.

Claims

Total claims: 26

Method of treatment claims: 26

Recent Review Articles

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The author declares no competing financial interest.