Synthesis, structure-activity relationships, antitumor activities and mechanistic studies of ENL-degrading compounds

Xin Li; Harshavardhan Reddy Kasireddy; Chandra Bhushan Mishra; Bala Krishna Moku; Yongcheng Song

doi:10.1016/j.ejmech.2026.118989

Synthesis, structure-activity relationships, antitumor activities and mechanistic studies of ENL-degrading compounds

Eur J Med Chem. 2026 Oct 15:316:118989. doi: 10.1016/j.ejmech.2026.118989. Epub 2026 May 19.

Authors

Xin Li¹, Harshavardhan Reddy Kasireddy², Chandra Bhushan Mishra², Bala Krishna Moku², Yongcheng Song³

Affiliations

¹ Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA.
² Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA.
³ Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA. Electronic address: ysong@bcm.edu.

PMID: 42218837
DOI: 10.1016/j.ejmech.2026.118989

Abstract

Transcription cofactor ENL is a novel target for MLL-rearranged (MLL-r) leukemia and other blood cancers. We designed and synthesized several series of ENL-degrading compounds. Cereblon-recruiting, proteolysis targeting chimera (PROTAC) compounds 1-6 and 14 can efficiently degrade and deplete ENL with DC₅₀ as low as 4.2 nM, but not its paralog AF9. Mechanistic studies showed that the lysine residues of ENL(173-190) are critical for selective ENL degradation. These compounds selectively inhibited proliferation of MLL-r leukemia and multiple myeloma cells with EC₅₀s as low as 130 nM. Depletion of ENL mimicked ENL-knockdown and significantly suppressed expression of MYC and its target genes, causing inhibited cell proliferation. Combination treatment with a BRD4 inhibitor was synergistic. Compound 14 underwent rapid metabolic degradations when exposed to human microsomes. More medicinal chemistry optimization is therefore needed in the perspective of drug discovery targeting MLL-r leukemia and other blood cancers.

Keywords: Cancer therapeutics; ENL; MLL-Rearranged leukemia; Multiple myeloma; Targeted protein degradation.

MeSH terms

Antineoplastic Agents* / chemical synthesis
Antineoplastic Agents* / chemistry
Antineoplastic Agents* / pharmacology
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Molecular Structure
Nuclear Proteins* / antagonists & inhibitors
Nuclear Proteins* / metabolism
Proteolysis / drug effects
Proteolysis Targeting Chimera
Structure-Activity Relationship
Transcription Factors / antagonists & inhibitors
Transcription Factors / metabolism
Transcriptional Elongation Factors* / antagonists & inhibitors
Transcriptional Elongation Factors* / metabolism

Substances

Antineoplastic Agents
Transcriptional Elongation Factors
ELL protein, human
Proteolysis Targeting Chimera
Nuclear Proteins
Transcription Factors