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

The C-C chemokine receptor 4 (CCR4) is broadly expressed on regulatory T cells (T) as well as other circulating and tissue-resident T cells. T can be recruited to the tumor microenvironment (TME) through the C-C chemokines CCL17 and CCL22. T 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.

Discovery of Potent, Selective, and Orally Bioavailable Inhibitors of USP7 with In Vivo Antitumor Activity.

USP7 is a promising target for cancer therapy as its inhibition is expected to decrease function of oncogenes, increase tumor suppressor function, and enhance immune function. Using a structure-based drug design strategy, a new class of reversible USP7 inhibitors has been identified that is highly potent in biochemical and cellular assays and extremely selective for USP7 over other deubiquitinases. The succinimide was identified as a key potency-driving motif, forming two strong hydrogen bonds to the allosteric pocket of USP7.

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

Recruitment of suppressive CD4 FOXP3 regulatory T cells (T) to the tumor microenvironment (TME) has the potential to weaken the antitumor response in patients receiving treatment with immuno-oncology (IO) agents. Human T express CCR4 and can be recruited to the TME through the CC chemokine ligands CCL17 and CCL22. In some cancers, T accumulation correlates with poor patient prognosis.