Discovery of a Potent and Selective STAT5 PROTAC Degrader with Strong Antitumor Activity In Vivo in Acute Myeloid Leukemia

Abstract

STAT5 is an attractive therapeutic target for human cancers. We report herein the discovery of a potent and selective STAT5 degrader with strong antitumor activity in vivo. We first obtained small-molecule ligands with sub-micromolar to low micromolar binding affinities to STAT5 and STAT6 SH2 domains and determined co-crystal structures of three such ligands in complex with STAT5A. We successfully transformed these ligands into potent and selective STAT5 degraders using the PROTAC technology with AK-2292 as the best compound. AK-2292 effectively induces degradation of STAT5A, STAT5B, and phosphorylated STAT5 proteins in a concentration- and time-dependent manner in acute myeloid leukemia (AML) cell lines and demonstrates excellent degradation selectivity for STAT5 over all other STAT members. It exerts potent and specific cell growth inhibitory activity in AML cell lines with high levels of phosphorylated STAT5. AK-2292 effectively reduces STAT5 protein in vivo and achieves strong antitumor activity in mice at well-tolerated dose schedules.

Precise Conformational Control Yielding Highly Potent and Exceptionally Selective BRD4 Degraders with Strong Antitumor Activity

“…One of the very attractive features of a PROTAC degrader molecule is its ability to achieve high degradation selectivity for one protein over its closely homologous proteins. ,,,,− This is due to the fact that a PROTAC degrader must form a productive ternary complex consisting of the degrader itself, the protein of interest (POI), and an E3 ligase, to achieve effective degradation of the POI . The formation of the productive ternary complex may involve protein surface residues from both the POI and the E3 ligase. ,, In contrast to the conserved binding site residues in homologous proteins, protein surface residues are not well conserved even among highly homologous proteins.…”

“…The requirement of formation of a productive ternary complex by engaging less conserved surface residues, therefore, provides an opportunity to achieve high selectivity for the POI over its highly homologous proteins with appropriately designed PROTAC degrader molecules. In addition to selective BRD4 degraders, ,, the PROTAC technology has been used for the successful discovery of potent and selective degraders for a number of traditionally undruggable or difficultly druggable therapeutic targets. − ,− We have previously reported the discovery of a highly selective and efficacious STAT3 PROTAC degrader using a modestly selective STAT3 ligand. , Two recent studies reported the discovery of selective SMARCA2 degraders over its close homologous SMARCA4 protein, which were designed using nonselective SMARCA2/4 ligands. , Using a ligand with no selectivity for STAT5 and STAT6 proteins, we recently reported our successful development of a potent, selective, and efficacious STAT5 PROTAC degrader over STAT6. , These studies highlight the power of the PROTAC technology to selectively target one protein over its highly homologous proteins.…”

PROTACs: A novel strategy for cancer drug discovery and development

“…Significantly, complete and lasting tumor regression was achieved by compound SD‐36 in a Molm‐16 xenograft tumor model with a well‐tolerated dose schedule. Very recently, the same group reported a new class of highly effective STAT5 degraders, typically by compound AK‐2292 (Table 1 and Figure 3; CRBN‐3) 327,328 . The most active compound AK‐2292 effectively induced degradation of STAT5A, STAT5B, and phosphorylated STAT5 proteins in AML cells in a concentration‐ and time‐dependent manner, and exhibited excellent degradation selectivity for STAT5 over all other STAT members.…”

Exploitation of Proximity-Mediated Effects in Drug Discovery: An Update of Recent Research Highlights in Perturbing Pathogenic Proteins and Correlated Issues

“…In another article, Wang and co-workers disclosed their detailed medicinal chemistry work that culminated in the discovery of 18 . Moreover, they characterized the efficacy of 18 in AML xenograft models and validated its capability to reduce the level of STAT5 in vivo . In addition to the aforementioned canonical PROTACs, researchers have developed OligoTRAFTACs and O′PROTACs as generalizable strategies for inducing the proteasomal degradation of TFs.…”