Novel Piperidinyl-Azetidines as Potent and Selective CCR4 Antagonists Elicit Antitumor Response as a Single Agent and in Combination with Checkpoint Inhibitors

Abstract

The C–C chemokine receptor 4 (CCR4) is broadly expressed on regulatory T cells (Treg) as well as other circulating and tissue-resident T cells. Treg can be recruited to the tumor microenvironment (TME) through the C–C chemokines CCL17 and CCL22. Treg accumulation in the TME has been shown to dampen the antitumor immune response and is thought to be an important driver in tumor immune evasion. Preclinical and clinical data suggest that reducing the Treg population in the TME can potentiate the antitumor immune response of checkpoint inhibitors. We have developed small-molecule antagonists of CCR4, featuring a novel piperidinyl-azetidine motif, that inhibit the recruitment of Treg into the TME and elicit antitumor responses as a single agent or in combination with an immune checkpoint blockade. The discovery of these potent, selective, and orally bioavailable CCR4 antagonists, and their activity in in vitro and in vivo models, is described herein.

Investigating Mechanisms of Response or Resistance to Immune Checkpoint Inhibitors by Analyzing Cell-Cell Communications in Tumors Before and After Programmed Cell Death-1 (PD-1) Targeted Therapy: An Integrative Analysis Using Single-cell RNA and Bulk-RNA Sequencing Data

“… 17 On the other hand, it was reported that antagonists of CCR4 could prevent the recruitment of Tregs into the TME and elicit antitumor responses in combination with anti-CTLA4 therapy. 39 In our study, the CCL5-CCR4 interaction between effector CD8 T cells/exhausted CD8 T cells/NK cells and CD4 T cells/proliferative T cells/Tregs was relatively stronger in nonresponders than in responders. A previous study showed that CCL4, a chemokine that recruits CD103+ DCs to the tumor by binding to CCR5, played a role in the response to ICIs.…”

Emerging Building Blocks for Medicinal Chemistry: Recent Synthetic Advances

“…The SuFEx reactions typically use common sulfonylation conditions (Et 3 N, CH 2 Cl 2 ); [130,[136][137][138][139] also, ammonia [140][141][142][143][144][145] or aliphatic amines [146][147][148][149][150][151] can act both as reagents and as bases (Scheme 15A). One more important modification includes reaction of sulfonyl halides and aliphatic N-silylamines in refluxing in MeCN.…”

“…Another extremely important derivative is 1-bromoethene sulfonyl fluoride (42, BESF) that can be easily obtained by bromination of the C=C bond of ESF with Br 2 in CH 2 Cl 2 or CHCl 3 , [171,295,296] followed by Et 3 N- [295] or i-Pr 2 NEt-mediated [171] elimination of HBr from 1,2-dibromoethanesulfonyl fluoride (43, DBESF) obtained at the first step (Scheme 19C). Synthesis of βenamino sulfonyl fluorides 44 was performed by the Michael addition [297] of aliphatic (typically secondary and cyclic derivatives [143,146,294,298] ) or (hetero)aromatic amines to β-position of ESF (39) followed by oxidation with MnO 2 (Scheme 20). [299] Promising building blocks could be obtained from bulk amino esters used.…”

CCR4 as a Therapeutic Target for Cancer Immunotherapy

“…It has also been shown that CCR4-expressing Treg cells are recruited into tumor tissues by CCL22 that is produced in the tumor microenvironment by tumor cells and tumor-associated macrophages [ 226 , 227 , 228 , 229 , 230 , 231 ]. In preclinical and clinical studies, depletion of Treg cells by anti-CCR4 or CCR4 antagonists has been shown to augment antitumor immunity [ 232 , 233 , 234 , 235 , 236 , 237 , 238 ]. The therapeutic efficacy of Mogamulizumab on ATLL and CTCLs is also considered to be partly due to depletion of immunosuppressive Treg cells.…”