2. Academic Validation
  3. Prioritization of Eleven-Nineteen-Leukemia Inhibitors as Orally Available Drug Candidates for Acute Myeloid Leukemia

Prioritization of Eleven-Nineteen-Leukemia Inhibitors as Orally Available Drug Candidates for Acute Myeloid Leukemia

  • J Med Chem. 2024 Nov 28;67(22):20100-20117. doi: 10.1021/acs.jmedchem.4c01337.
Xuejiao Shirley Guo 1,  Sandeep Atla 1,  Satyanarayana Nyalata 1,  Yugendar R Alugubelli 1,  Peng-Hsun Chase Chen 1,  Shiqing Xu 1 2,  Wenshe Ray Liu 1 2 3 4 5
Affiliations

Affiliations

  • 1 Texas A&M Drug Discovery Center and Department of Chemistry, Texas A&M University, College Station, Texas 77843, United States.
  • 2 Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy, Texas A&M University, College Station, Texas 77843, United States.
  • 3 Institute of Biosciences and Technology and Department of Translational Medical Sciences, College of Medicine, Texas A&M University, Houston, Texas 77030, United States.
  • 4 Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas 77843, United States.
  • 5 Department of Cell Biology and Genetics, College of Medicine, Texas A&M University, Bryan, Texas 77807, United States.
PMID: 39530508 DOI: 10.1021/acs.jmedchem.4c01337
Abstract

Acute myeloid leukemia (AML) is the second most prevalent and fatal form of leukemia. The growth of AML cells harboring oncogenic MLL rearrangements relies on the YEATS domain-containing protein ENL. Many small molecule inhibitors targeting ENL have been developed. To prioritize these inhibitors for in vivo studies, a NanoBRET system was introduced to evaluate their cellular permeability and potency. This screening identified inhibitor 13 as a promising candidate. This inhibitor has remarkable metabolic stability and potent antiproliferative effects on MLL-fusion leukemia cell lines. In AML-xenografted mice, inhibitor 13 significantly improved survival. Subsequent optimization efforts led to the development of SR-C-107 (R), which exhibited strong activity against AML both at the cellular level (CC50 (MOLM-13): 1.25 ± 0.18 μM; CC50 (MV4-11): 0.81 ± 0.15 μM) and in vivo. These findings establish SR-C-107 (R) as a compelling candidate for AML treatment and lay the groundwork for the development of next-generation AML inhibitors.

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