Identification of Novel Potent NSD2-PWWP1 Ligands Using Structure-Based Design and Computational Approaches

Abstract

Dysregulation of histone methyl transferase nuclear receptor-binding SET domain 2 (NSD2) has been implicated in several hematological and solid malignancies. NSD2 is a large multidomain protein that carries histone writing and histone reading functions. To date, identifying inhibitors of the enzymatic activity of NSD2 has proven challenging in terms of potency and SET domain selectivity. Inhibition of the NSD2-PWWP1 domain using small molecules has been considered as an alternative approach to reduce NSD2-unregulated activity. In this article, we present novel computational chemistry approaches, encompassing free energy perturbation coupled to machine learning (FEP/ML) models as well as virtual screening (VS) activities, to identify high-affinity NSD2 PWWP1 binders. Through these activities, we have identified the most potent NSD2-PWWP1 binder reported so far in the literature: compound 34 (pIC50 = 8.2). The compounds identified herein represent useful tools for studying the role of PWWP1 domains for inhibition of human NSD2.

Discovery of a Highly Potent Lysine Methyltransferases G9a/NSD2 Dual Inhibitor to Treat Solid Tumors

“…NSD2 is composed of multiple domains, including the catalytic SET domain, five plant homeodomain domains, and two proline-tryptophan-tryptophan-proline domains (PWWP1 and PWWP2). Until now, several small-molecule inhibitors and degraders have been developed by targeting one of these domains, − as presented by compounds 8–13 . Intriguingly, one analogue of compound 13 , KTX-1001 (structure not disclosed) has been recently advanced into clinical trial in patients with relapsed and refractory MM (NCT05651932).…”