TY - JOUR
T1 - Development of small molecule inhibitors targeting PBX1 transcription signaling as a novel cancer therapeutic strategy
AU - Shen, Yao An
AU - Jung, Jin
AU - Shimberg, Geoffrey D.
AU - Hsu, Fang Chi
AU - Rahmanto, Yohan Suryo
AU - Gaillard, Stephanie L.
AU - Hong, Jiaxin
AU - Bosch, Jürgen
AU - Shih, Ie Ming
AU - Chuang, Chi Mu
AU - Wang, Tian Li
N1 - Funding Information:
This work was supported by the NIH grants R01CA148826 , R01CA215483 , R21CA187512 , and P50CA228991 ; the Department of Defense grants W81XWH-11-2-0230 and W81XWH-14-1-0221 ; the Ovarian Cancer Research Alliance award; the Maryland Innovation Initiative MII (TEDCO); the Bisciotti Foundation Translational Fund; the Richard W. TeLinde endowment from the Department of Gynecology and Obstetrics, Johns Hopkins University , and the TEAL Award. G.D.S. is a recipient of the T32 fellowship award ( NIH / NIA T32AG058527 ). We thank Biacore Molecular Interaction Shared Resource at Georgetown University , which is partially supported by NIH grant P30CA051008 and S10 shared instrument grants 1S10OD019982-01 and 1S10RR022388-01 .
Funding Information:
This work was supported by the NIH grants R01CA148826, R01CA215483, R21CA187512, and P50CA228991; the Department of Defense grants W81XWH-11-2-0230 and W81XWH-14-1-0221; the Ovarian Cancer Research Alliance award; the Maryland Innovation Initiative MII (TEDCO); the Bisciotti Foundation Translational Fund; the Richard W. TeLinde endowment from the Department of Gynecology and Obstetrics, Johns Hopkins University, and the TEAL Award. G.D.S. is a recipient of the T32 fellowship award (NIH/NIA T32AG058527). We thank Biacore Molecular Interaction Shared Resource at Georgetown University, which is partially supported by NIH grant P30CA051008 and S10 shared instrument grants 1S10OD019982-01 and 1S10RR022388-01. Y.-A.S. J.J. G.D.S. Y.S.R. and J.H. conducted the experiments described in the paper. J.B. conducted computational screening. F.-C.H. performed RNA-seq bioinformatics analysis. I.-M.S. and T.-L.W. conceived the study and were in charge of the overall study design and research direction. C.-M.C. Y.-A.S. J.J. G.D.S. S.L.G. I.-M.S. and T.-L.W. wrote the manuscript. All authors reviewed the manuscript, agreed with results, and provided comments on the manuscript. T.-L.W. is the founder of Ovata, Incov. T.-L.W. and I.-M.S. have a patent related to this work. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in science.
Publisher Copyright:
© 2021 The Authors
PY - 2021/11/19
Y1 - 2021/11/19
N2 - PBX1 is a transcription factor involved in diverse cellular functions including organ development, stem cell renewal, and tumorigenesis. PBX1 is localized at chr1q23.3, a frequently amplified chromosomal region, and it is overexpressed in many human malignancies. Cancer cells with elevated PBX1 signaling are particularly vulnerable to PBX1 withdrawal. We designed a series of small molecule compounds capable of docking to the interface between PBX1 and its cognate DNA target sequence. Among them, T417 is found to be a lead compound. In cell-based assays, T417 significantly suppressed self-renewal and proliferation of cancer cells expressing high levels of PBX1. T417 also re-sensitized platinum-resistant ovarian tumors to carboplatin. T417 did not affect healthy tissues likely due to their lower PBX1 expression levels. Therefore, targeting PBX-DNA interface can be a promising strategy for treating human tumors reliant on PBX1 for survival.
AB - PBX1 is a transcription factor involved in diverse cellular functions including organ development, stem cell renewal, and tumorigenesis. PBX1 is localized at chr1q23.3, a frequently amplified chromosomal region, and it is overexpressed in many human malignancies. Cancer cells with elevated PBX1 signaling are particularly vulnerable to PBX1 withdrawal. We designed a series of small molecule compounds capable of docking to the interface between PBX1 and its cognate DNA target sequence. Among them, T417 is found to be a lead compound. In cell-based assays, T417 significantly suppressed self-renewal and proliferation of cancer cells expressing high levels of PBX1. T417 also re-sensitized platinum-resistant ovarian tumors to carboplatin. T417 did not affect healthy tissues likely due to their lower PBX1 expression levels. Therefore, targeting PBX-DNA interface can be a promising strategy for treating human tumors reliant on PBX1 for survival.
KW - Cancer
KW - Chemistry
UR - http://www.scopus.com/inward/record.url?scp=85118856605&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85118856605&partnerID=8YFLogxK
U2 - 10.1016/j.isci.2021.103297
DO - 10.1016/j.isci.2021.103297
M3 - Article
AN - SCOPUS:85118856605
SN - 2589-0042
VL - 24
JO - iScience
JF - iScience
IS - 11
M1 - 103297
ER -
