Discovery of a Potent and Selective CCR4 Antagonist That Inhibits T_reg Trafficking into the Tumor Microenvironment

Abstract

Recruitment of suppressive CD4+ FOXP3+ regulatory T cells (Treg) to the tumor microenvironment (TME) has the potential to weaken the antitumor response in patients receiving treatment with immuno-oncology (IO) agents. Human Treg express CCR4 and can be recruited to the TME through the CC chemokine ligands CCL17 and CCL22. In some cancers, Treg accumulation correlates with poor patient prognosis. Preclinical data suggests that preventing the recruitment of Treg and increasing the population of activated effector T cells (Teff) in the TME can potentiate antitumor immune responses. We developed a novel series of potent, orally bioavailable small molecule antagonists of CCR4. From this series, several compounds exhibited high potency in distinct functional assays in addition to good in vitro and in vivo ADME properties. The design, synthesis, and SAR of this series and confirmation of its in vivo activity are reported.

Regulatory T cells in tumor microenvironment: new mechanisms, potential therapeutic strategies and future prospects

“…Human Tregs express CCR4 and can be recruited to the TME through CCL17 and CCL22. In some cancers, Tregs accumulation correlates with poor patient prognosis [ 157 ]. Infiltration of Tregs was caused by the interaction between the tumour-producing chemokine CCL17 and receptor CCR4 expressed on Tregs in dogs bearing spontaneous bladder cancer.…”

Hypoxia Alters the Expression of CC Chemokines and CC Chemokine Receptors in a Tumor–A Literature Review

“…Similarly, because of a significant pro-cancer effect, it is postulated that treatment may target the functioning of CCL3/MIP-1α [19,255], CCL5/RANTES [45,256]. Another therapeutic approach is the use of anti-CCR4 antibodies or CCR4 antagonists ( receptor for CCL17/TARC and CCL22/MDC) in cancer therapy [257][258][259] to reduce the accumulation of T reg and thus enhance the immunotherapy and anticancer response of the immune system. Some researchers also postulate targeting the CCL20/LARC→CCR6 axis [260,261], which causes chemoresistance and migration of neoplastic cells, and so any disorder in the function of CCL20/LARC should increase the activity of anticancer drugs.…”

“…Similarly, because of a significant pro-cancer effect, it is postulated that treatment may target the functioning of CCL3/MIP-1α [ 19 , 255 ], CCL5/RANTES [ 45 , 256 ]. Another therapeutic approach is the use of anti-CCR4 antibodies or CCR4 antagonists (receptor for CCL17/TARC and CCL22/MDC) in cancer therapy [ 257 , 258 , 259 ] to reduce the accumulation of T reg and thus enhance the immunotherapy and anticancer response of the immune system.…”

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

“…Over the past decade, several small-molecule CCR4 antagonists have been reported. These antagonists can be grouped into two classes based on their proposed binding sites. − Class I antagonists ( 1 – 4a , b , − Figure ), which feature a heterocyclic core decorated with a lipophilic substituent and an amine-containing side chain, bind extracellularly at the allosteric antagonist binding site I. Class II antagonists ( 5 – 6a , b , , Figure ), containing a heterocyclic core substituted with a sulfonamide side chain and a lipophilic motif, bind intracellularly at the allosteric antagonist binding site II.…”

“…These class I antagonists featured a novel pyrazolopyrazine core with a unique cyclohexenyl side chain ( 4a , b , Figure ). Although 4b inhibited the migration of T reg in both in vitro and in vivo models, it suffered from high clearance in rats and also required high doses to achieve significant reduction of T reg migration in mouse models. While 4b was a suitable tool compound for proof of concept experiments, we wanted to advance our program by discovering a more simplified side chain.…”