TY - JOUR
T1 - Chemical Inhibition of ENL/AF9 YEATS Domains in Acute Leukemia
AU - Garnar-Wortzel, Leopold
AU - Bishop, Timothy R.
AU - Kitamura, Seiya
AU - Milosevich, Natalia
AU - Asiaban, Joshua N.
AU - Zhang, Xiaoyu
AU - Zheng, Qinheng
AU - Chen, Emily
AU - Ramos, Anissa R.
AU - Ackerman, Christopher J.
AU - Hampton, Eric N.
AU - Chatterjee, Arnab K.
AU - Young, Travis S.
AU - Hull, Mitchell V.
AU - Sharpless, K. Barry
AU - Cravatt, Benjamin F.
AU - Wolan, Dennis W.
AU - Erb, Michael A.
N1 - Funding Information:
We gratefully acknowledge L. L. Lairson for critically reading the manuscript; G. E. Winter for helpful discussions regarding the work; L. L. Lairson, P. G. Schultz, and I. A. Wilson for access to the instrumentation. We also thank P. G. Schultz and the Schultz laboratory for helpful discussions and technical support. Sequencing was performed by the Scripps Research Next Generation Sequencing Core (La Jolla). This work was supported by the National Institutes of Health (NIH) through an NIH Director’s Early Independence Award (DP5-OD26380) to M.A.E., by the Leukemia and Lymphoma Society through a New Idea Award to M.A.E. and by the Ono Pharma Foundation to M.A.E. Research reported in this publication was also supported by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number K99GM138758 (S.K.).
Publisher Copyright:
© 2021 The Authors. Published by American Chemical Society.
PY - 2021/5/26
Y1 - 2021/5/26
N2 - Transcriptional coregulators, which mediate chromatin-dependent transcriptional signaling, represent tractable targets to modulate tumorigenic gene expression programs with small molecules. Genetic loss-of-function studies have recently implicated the transcriptional coactivator, ENL, as a selective requirement for the survival of acute leukemia and highlighted an essential role for its chromatin reader YEATS domain. Motivated by these discoveries, we executed a screen of nearly 300,000 small molecules and identified an amido-imidazopyridine inhibitor of the ENL YEATS domain (IC50 = 7 μM). Improvements to the initial screening hit were enabled by adopting and expanding upon a SuFEx-based approach to high-throughput medicinal chemistry, ultimately demonstrating that it is compatible with cell-based drug discovery. Through these efforts, we discovered SR-0813, a potent and selective ENL/AF9 YEATS domain inhibitor (IC50 = 25 nM). Armed with this tool and a first-in-class ENL PROTAC, SR-1114, we detailed the biological response of AML cells to pharmacological ENL disruption for the first time. Most notably, we discovered that ENL YEATS inhibition is sufficient to selectively suppress ENL target genes, including HOXA9/10, MYB, MYC, and a number of other leukemia proto-oncogenes. Cumulatively, our study establishes YEATS domain inhibition as a viable approach to disrupt the pathogenic function of ENL in acute leukemia and provides the first thoroughly characterized chemical probe for the ENL YEATS domain.
AB - Transcriptional coregulators, which mediate chromatin-dependent transcriptional signaling, represent tractable targets to modulate tumorigenic gene expression programs with small molecules. Genetic loss-of-function studies have recently implicated the transcriptional coactivator, ENL, as a selective requirement for the survival of acute leukemia and highlighted an essential role for its chromatin reader YEATS domain. Motivated by these discoveries, we executed a screen of nearly 300,000 small molecules and identified an amido-imidazopyridine inhibitor of the ENL YEATS domain (IC50 = 7 μM). Improvements to the initial screening hit were enabled by adopting and expanding upon a SuFEx-based approach to high-throughput medicinal chemistry, ultimately demonstrating that it is compatible with cell-based drug discovery. Through these efforts, we discovered SR-0813, a potent and selective ENL/AF9 YEATS domain inhibitor (IC50 = 25 nM). Armed with this tool and a first-in-class ENL PROTAC, SR-1114, we detailed the biological response of AML cells to pharmacological ENL disruption for the first time. Most notably, we discovered that ENL YEATS inhibition is sufficient to selectively suppress ENL target genes, including HOXA9/10, MYB, MYC, and a number of other leukemia proto-oncogenes. Cumulatively, our study establishes YEATS domain inhibition as a viable approach to disrupt the pathogenic function of ENL in acute leukemia and provides the first thoroughly characterized chemical probe for the ENL YEATS domain.
UR - http://www.scopus.com/inward/record.url?scp=85106621450&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85106621450&partnerID=8YFLogxK
U2 - 10.1021/acscentsci.0c01550
DO - 10.1021/acscentsci.0c01550
M3 - Article
C2 - 34079898
AN - SCOPUS:85106621450
SN - 2374-7943
VL - 7
SP - 815
EP - 830
JO - ACS Central Science
JF - ACS Central Science
IS - 5
ER -