Discovery and Preclinical Pharmacology of NX-2127, an Orally Bioavailable Degrader of Bruton's Tyrosine Kinase with Immunomodulatory Activity for the Treatment of Patients with B Cell Malignancies.

Bruton's tyrosine kinase (BTK), a member of the TEC family of kinases, is an essential effector of B-cell receptor (BCR) signaling. Chronic activation of BTK-mediated BCR signaling is a hallmark of many hematological malignancies, which makes it an attractive therapeutic target. Pharmacological inhibition of BTK enzymatic function is now a well-proven strategy for the treatment of patients with these malignancies.

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 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.