Development of small molecule inhibitors targeting PBX1 transcription signaling as a novel cancer therapeutic strategy

Yao An Shen; Jin Jung; Geoffrey D. Shimberg; Fang Chi Hsu; Yohan Suryo Rahmanto; Stephanie L. Gaillard; Jiaxin Hong; Jürgen Bosch; Ie Ming Shih; Chi Mu Chuang; Tian Li Wang

doi:10.1016/j.isci.2021.103297

Development of small molecule inhibitors targeting PBX1 transcription signaling as a novel cancer therapeutic strategy

Yao An Shen
, Jin Jung
, Geoffrey D. Shimberg
, Fang Chi Hsu
, Yohan Suryo Rahmanto
, Stephanie L. Gaillard
, Jiaxin Hong
, Jürgen Bosch
, Ie Ming Shih
, Chi Mu Chuang
, Tian Li Wang

Research output: Contribution to journal › Article › peer-review

23 Citations (Scopus)

Abstract

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.

Original language	English
Article number	103297
Journal	iScience
Volume	24
Issue number	11
DOIs	https://doi.org/10.1016/j.isci.2021.103297
Publication status	Published - Nov 19 2021

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Cancer
Chemistry

ASJC Scopus subject areas

General

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10.1016/j.isci.2021.103297

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@article{b572ba7faee64884bc73e14c0526feaf,

title = "Development of small molecule inhibitors targeting PBX1 transcription signaling as a novel cancer therapeutic strategy",

abstract = "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.",

keywords = "Cancer, Chemistry",

author = "Shen, \{Yao An\} and Jin Jung and Shimberg, \{Geoffrey D.\} and Hsu, \{Fang Chi\} and Rahmanto, \{Yohan Suryo\} and Gaillard, \{Stephanie L.\} and Jiaxin Hong and J{\"u}rgen Bosch and Shih, \{Ie Ming\} and Chuang, \{Chi Mu\} and Wang, \{Tian Li\}",

note = "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: {\textcopyright} 2021 The Authors",

year = "2021",

month = nov,

day = "19",

doi = "10.1016/j.isci.2021.103297",

language = "English",

volume = "24",

journal = "iScience",

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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 - https://www.scopus.com/pages/publications/85118856605

UR - https://www.scopus.com/pages/publications/85118856605#tab=citedBy

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 -

Development of small molecule inhibitors targeting PBX1 transcription signaling as a novel cancer therapeutic strategy

Abstract

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Keywords

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