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  3. Targeting lipid-protein interaction to treat Syk-mediated acute myeloid leukemia

Targeting lipid-protein interaction to treat Syk-mediated acute myeloid leukemia

  • Nat Chem Biol. 2022 Oct 13. doi: 10.1038/s41589-022-01150-z.
Indira Singaram # 1,  Ashutosh Sharma # 1,  Shashank Pant 2 3,  Muyun Lihan 2,  Mi-Jeong Park 4,  Melissa Pergande 1,  Pawanthi Buwaneka 1,  Yusi Hu 1 5,  Nadim Mahmud 6,  You-Me Kim 7,  Stephanie Cologna 1,  Vladimir Gevorgyan 8,  Irum Khan 6,  Emad Tajkhorshid 2,  Wonhwa Cho 9
Affiliations

Affiliations

  • 1 Department of Chemistry, University of Illinois Chicago (UIC), Chicago, IL, USA.
  • 2 NIH Center for Macromolecular Modeling and Bioinformatics, Beckman Institute for Advanced Science and Technology, Department of Biochemistry, Center for Biophysics and Quantitative Biology, University of Illinois Urbana-Champaign, Urbana, IL, USA.
  • 3 Loxo Oncology @ Lilly, Louisville, CO, USA.
  • 4 Department of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, Republic of Korea.
  • 5 College of Chemistry and School of Medicine, Nankai University, Tianjin, P. R. China.
  • 6 Department of Medicine, University of Illinois Chicago, Chicago, IL, USA.
  • 7 Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
  • 8 Department of Chemistry, University of Texas at Dallas, Dallas, TX, USA.
  • 9 Department of Chemistry, University of Illinois Chicago (UIC), Chicago, IL, USA. wcho@uic.edu.
  • # Contributed equally.
PMID: 36229686 DOI: 10.1038/s41589-022-01150-z
Abstract

Membrane lipids control the cellular activity of kinases containing the Src homology 2 (SH2) domain through direct lipid-SH2 domain interactions. Here we report development of new nonlipidic small molecule inhibitors of the lipid-SH2 domain interaction that block the cellular activity of their host proteins. As a pilot study, we evaluated the efficacy of lipid-SH2 domain interaction inhibitors for spleen tyrosine kinase (Syk), which is implicated in hematopoietic malignancies, including acute myeloid leukemia (AML). An optimized inhibitor (WC36) specifically and potently suppressed oncogenic activities of Syk in AML cell lines and patient-derived AML cells. Unlike ATP-competitive Syk inhibitors, WC36 was refractory to de novo and acquired drug resistance due to its ability to block not only the Syk kinase activity, but also its noncatalytic scaffolding function that is linked to drug resistance. Collectively, our study shows that targeting lipid-protein interaction is a powerful approach to developing new small molecule drugs.

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