Small-Molecule MYC Inhibitors Suppress Tumor Growth and Enhance Immunotherapy

Huiying Han; Atul D. Jain; Mihai I. Truica; Javier Izquierdo-Ferrer; Jonathan F. Anker; Barbara Lysy; Vinay Sagar; Yi Luan; Zachary R. Chalmers; Kenji Unno; Hanlin Mok; Rajita Vatapalli; Young A. Yoo; Yara Rodriguez; Irawati Kandela; J. Brandon Parker; Debabrata Chakravarti; Rama K. Mishra; Gary E. Schiltz; Sarki A. Abdulkadir

doi:10.1016/j.ccell.2019.10.001

Small-Molecule MYC Inhibitors Suppress Tumor Growth and Enhance Immunotherapy

Huiying Han, Atul D. Jain, Mihai I. Truica, Javier Izquierdo-Ferrer, Jonathan F. Anker, Barbara Lysy, Vinay Sagar, Yi Luan, Zachary R. Chalmers, Kenji Unno, Hanlin Mok, Rajita Vatapalli, Young A. Yoo, Yara Rodriguez, Irawati Kandela, J. Brandon Parker, Debabrata Chakravarti, Rama K. Mishra, Gary E. Schiltz, Sarki A. Abdulkadir^*

^*Corresponding author for this work

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

285 Scopus citations

Abstract

Small molecules that directly target MYC and are also well tolerated in vivo will provide invaluable chemical probes and potential anti-cancer therapeutic agents. We developed a series of small-molecule MYC inhibitors that engage MYC inside cells, disrupt MYC/MAX dimers, and impair MYC-driven gene expression. The compounds enhance MYC phosphorylation on threonine-58, consequently increasing proteasome-mediated MYC degradation. The initial lead, MYC inhibitor 361 (MYCi361), suppressed in vivo tumor growth in mice, increased tumor immune cell infiltration, upregulated PD-L1 on tumors, and sensitized tumors to anti-PD1 immunotherapy. However, 361 demonstrated a narrow therapeutic index. An improved analog, MYCi975 showed better tolerability. These findings suggest the potential of small-molecule MYC inhibitors as chemical probes and possible anti-cancer therapeutic agents.

Original language	English (US)
Pages (from-to)	483-497.e15
Journal	Cancer cell
Volume	36
Issue number	5
DOIs	https://doi.org/10.1016/j.ccell.2019.10.001
State	Published - Nov 11 2019

Funding

We thank Dr. Edward V. Prochownik for constructs and compound JKY-2-169, Dr. Shideng Bao for MYC mutant constructs, Dr. Chi V. Dang for P493-6 B cells, and Dr. John M. Sedivy for Rat-1 fibroblast cells. We thank the NUseq and the Robert H. Lurie Comprehensive Cancer Center Flow Cytometry cores of Northwestern University. We thank Dr. Andrew Mazar and Dr. Nicolette Zielinski for helpful discussions on the project design and Lisa Hurley for the technical assistance. This work was supported by grants from the National Cancer Institute: R01CA123484, RO1CA196270, and P50CA180995; and by the NewCures Biomedical Accelerator of Northwestern University. Part of the work was supported by the H-Foundation Multi-PI Basic Science Synergy Award made possible by a gift from the H Foundation to the Robert H. Lurie Comprehensive Cancer Center. A part of this work was performed by the Northwestern University ChemCore and the Developmental Therapeutics Core, which are funded by Cancer Center Support Grant P30CA060553 from the National Cancer Institute awarded to the Robert H. Lurie Comprehensive Cancer Center, and the Chicago Biomedical Consortium with support from the Searle Funds at the Chicago Community Trust. H.H. G.E.S. R.K.M. and S.A.A conceived and designed the experiments. R.K.M. designed and performed in silico screening. G.E.S. supervised the chemical aspects of these studies. H.H. conducted most of the in vitro and in vivo biological experiments. A.D.J. and J.I.-F. synthesized compounds and performed STD NMR experiments. M.I.T. performed fluorescence polarization assay and in vitro kinase assay. H.M. helped in western blot experiments. J.F.A. performed immune cells flow cytometry analysis. K.U. performed organoid culture experiment. B.L. V.S. Y.L. Y.R. R.V. Y.A.Y. and I.K. assisted in biological studies and data analysis. Z.R.C. analyzed RNA-seq data. J.B.P. and D.C. contributed to data interpretation. S.A.A. supervised the overall project. H.H. S.A.A. M.I.T. G.E.S. and A.D.J. wrote the manuscript, with input from all the other authors. H.H. A.D.J. J.I. R.K.M. G.E.S. and S.A.A. are co-inventors on patent applications covering the methods and assays to identify and characterize MYC inhibitors and derivatives. All other authors declare no competing interests. We thank Dr. Edward V. Prochownik for constructs and compound JKY-2-169, Dr. Shideng Bao for MYC mutant constructs, Dr. Chi V. Dang for P493-6 B cells, and Dr. John M. Sedivy for Rat-1 fibroblast cells. We thank the NUseq and the Robert H. Lurie Comprehensive Cancer Center Flow Cytometry cores of Northwestern University. We thank Dr. Andrew Mazar and Dr. Nicolette Zielinski for helpful discussions on the project design and Lisa Hurley for the technical assistance. This work was supported by grants from the National Cancer Institute : R01CA123484 , RO1CA196270 , and P50CA180995 ; and by the NewCures Biomedical Accelerator of Northwestern University . Part of the work was supported by the H-Foundation Multi-PI Basic Science Synergy Award made possible by a gift from the H Foundation to the Robert H. Lurie Comprehensive Cancer Center. A part of this work was performed by the Northwestern University ChemCore and the Developmental Therapeutics Core, which are funded by Cancer Center Support Grant P30CA060553 from the National Cancer Institute awarded to the Robert H. Lurie Comprehensive Cancer Center, and the Chicago Biomedical Consortium with support from the Searle Funds at the Chicago Community Trust.

Keywords

MYC
MYC degradation
MYC-threonine 58 phosphorylation
PD-L1
anti-PD1
cancer therapy
immunotherapy
in silico screen
small molecules
target engagement

ASJC Scopus subject areas

Oncology
Cell Biology
Cancer Research

UN SDGs

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

Access to Document

10.1016/j.ccell.2019.10.001

Cite this

Han, H., Jain, A. D., Truica, M. I., Izquierdo-Ferrer, J., Anker, J. F., Lysy, B., Sagar, V., Luan, Y., Chalmers, Z. R., Unno, K., Mok, H., Vatapalli, R., Yoo, Y. A., Rodriguez, Y., Kandela, I., Parker, J. B., Chakravarti, D., Mishra, R. K., Schiltz, G. E., & Abdulkadir, S. A. (2019). Small-Molecule MYC Inhibitors Suppress Tumor Growth and Enhance Immunotherapy. Cancer cell, 36(5), 483-497.e15. https://doi.org/10.1016/j.ccell.2019.10.001

@article{253528bd946d4dae833b9c7d1db0d774,

title = "Small-Molecule MYC Inhibitors Suppress Tumor Growth and Enhance Immunotherapy",

abstract = "Small molecules that directly target MYC and are also well tolerated in vivo will provide invaluable chemical probes and potential anti-cancer therapeutic agents. We developed a series of small-molecule MYC inhibitors that engage MYC inside cells, disrupt MYC/MAX dimers, and impair MYC-driven gene expression. The compounds enhance MYC phosphorylation on threonine-58, consequently increasing proteasome-mediated MYC degradation. The initial lead, MYC inhibitor 361 (MYCi361), suppressed in vivo tumor growth in mice, increased tumor immune cell infiltration, upregulated PD-L1 on tumors, and sensitized tumors to anti-PD1 immunotherapy. However, 361 demonstrated a narrow therapeutic index. An improved analog, MYCi975 showed better tolerability. These findings suggest the potential of small-molecule MYC inhibitors as chemical probes and possible anti-cancer therapeutic agents.",

keywords = "MYC, MYC degradation, MYC-threonine 58 phosphorylation, PD-L1, anti-PD1, cancer therapy, immunotherapy, in silico screen, small molecules, target engagement",

author = "Huiying Han and Jain, {Atul D.} and Truica, {Mihai I.} and Javier Izquierdo-Ferrer and Anker, {Jonathan F.} and Barbara Lysy and Vinay Sagar and Yi Luan and Chalmers, {Zachary R.} and Kenji Unno and Hanlin Mok and Rajita Vatapalli and Yoo, {Young A.} and Yara Rodriguez and Irawati Kandela and Parker, {J. Brandon} and Debabrata Chakravarti and Mishra, {Rama K.} and Schiltz, {Gary E.} and Abdulkadir, {Sarki A.}",

note = "Funding Information: We thank Dr. Edward V. Prochownik for constructs and compound JKY-2-169, Dr. Shideng Bao for MYC mutant constructs, Dr. Chi V. Dang for P493-6 B cells, and Dr. John M. Sedivy for Rat-1 fibroblast cells. We thank the NUseq and the Robert H. Lurie Comprehensive Cancer Center Flow Cytometry cores of Northwestern University. We thank Dr. Andrew Mazar and Dr. Nicolette Zielinski for helpful discussions on the project design and Lisa Hurley for the technical assistance. This work was supported by grants from the National Cancer Institute: R01CA123484, RO1CA196270, and P50CA180995; and by the NewCures Biomedical Accelerator of Northwestern University. Part of the work was supported by the H-Foundation Multi-PI Basic Science Synergy Award made possible by a gift from the H Foundation to the Robert H. Lurie Comprehensive Cancer Center. A part of this work was performed by the Northwestern University ChemCore and the Developmental Therapeutics Core, which are funded by Cancer Center Support Grant P30CA060553 from the National Cancer Institute awarded to the Robert H. Lurie Comprehensive Cancer Center, and the Chicago Biomedical Consortium with support from the Searle Funds at the Chicago Community Trust. H.H. G.E.S. R.K.M. and S.A.A conceived and designed the experiments. R.K.M. designed and performed in silico screening. G.E.S. supervised the chemical aspects of these studies. H.H. conducted most of the in vitro and in vivo biological experiments. A.D.J. and J.I.-F. synthesized compounds and performed STD NMR experiments. M.I.T. performed fluorescence polarization assay and in vitro kinase assay. H.M. helped in western blot experiments. J.F.A. performed immune cells flow cytometry analysis. K.U. performed organoid culture experiment. B.L. V.S. Y.L. Y.R. R.V. Y.A.Y. and I.K. assisted in biological studies and data analysis. Z.R.C. analyzed RNA-seq data. J.B.P. and D.C. contributed to data interpretation. S.A.A. supervised the overall project. H.H. S.A.A. M.I.T. G.E.S. and A.D.J. wrote the manuscript, with input from all the other authors. H.H. A.D.J. J.I. R.K.M. G.E.S. and S.A.A. are co-inventors on patent applications covering the methods and assays to identify and characterize MYC inhibitors and derivatives. All other authors declare no competing interests. Funding Information: We thank Dr. Edward V. Prochownik for constructs and compound JKY-2-169, Dr. Shideng Bao for MYC mutant constructs, Dr. Chi V. Dang for P493-6 B cells, and Dr. John M. Sedivy for Rat-1 fibroblast cells. We thank the NUseq and the Robert H. Lurie Comprehensive Cancer Center Flow Cytometry cores of Northwestern University. We thank Dr. Andrew Mazar and Dr. Nicolette Zielinski for helpful discussions on the project design and Lisa Hurley for the technical assistance. This work was supported by grants from the National Cancer Institute : R01CA123484 , RO1CA196270 , and P50CA180995 ; and by the NewCures Biomedical Accelerator of Northwestern University . Part of the work was supported by the H-Foundation Multi-PI Basic Science Synergy Award made possible by a gift from the H Foundation to the Robert H. Lurie Comprehensive Cancer Center. A part of this work was performed by the Northwestern University ChemCore and the Developmental Therapeutics Core, which are funded by Cancer Center Support Grant P30CA060553 from the National Cancer Institute awarded to the Robert H. Lurie Comprehensive Cancer Center, and the Chicago Biomedical Consortium with support from the Searle Funds at the Chicago Community Trust. Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",

year = "2019",

month = nov,

day = "11",

doi = "10.1016/j.ccell.2019.10.001",

language = "English (US)",

volume = "36",

pages = "483--497.e15",

journal = "Cancer cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "5",

}

Han, H, Jain, AD, Truica, MI, Izquierdo-Ferrer, J, Anker, JF, Lysy, B, Sagar, V, Luan, Y, Chalmers, ZR, Unno, K, Mok, H, Vatapalli, R, Yoo, YA, Rodriguez, Y, Kandela, I, Parker, JB , Chakravarti, D , Mishra, RK , Schiltz, GE & Abdulkadir, SA 2019, 'Small-Molecule MYC Inhibitors Suppress Tumor Growth and Enhance Immunotherapy', Cancer cell, vol. 36, no. 5, pp. 483-497.e15. https://doi.org/10.1016/j.ccell.2019.10.001

TY - JOUR

T1 - Small-Molecule MYC Inhibitors Suppress Tumor Growth and Enhance Immunotherapy

AU - Han, Huiying

AU - Jain, Atul D.

AU - Truica, Mihai I.

AU - Izquierdo-Ferrer, Javier

AU - Anker, Jonathan F.

AU - Lysy, Barbara

AU - Sagar, Vinay

AU - Luan, Yi

AU - Chalmers, Zachary R.

AU - Unno, Kenji

AU - Mok, Hanlin

AU - Vatapalli, Rajita

AU - Yoo, Young A.

AU - Rodriguez, Yara

AU - Kandela, Irawati

AU - Parker, J. Brandon

AU - Chakravarti, Debabrata

AU - Mishra, Rama K.

AU - Schiltz, Gary E.

AU - Abdulkadir, Sarki A.

N1 - Funding Information: We thank Dr. Edward V. Prochownik for constructs and compound JKY-2-169, Dr. Shideng Bao for MYC mutant constructs, Dr. Chi V. Dang for P493-6 B cells, and Dr. John M. Sedivy for Rat-1 fibroblast cells. We thank the NUseq and the Robert H. Lurie Comprehensive Cancer Center Flow Cytometry cores of Northwestern University. We thank Dr. Andrew Mazar and Dr. Nicolette Zielinski for helpful discussions on the project design and Lisa Hurley for the technical assistance. This work was supported by grants from the National Cancer Institute: R01CA123484, RO1CA196270, and P50CA180995; and by the NewCures Biomedical Accelerator of Northwestern University. Part of the work was supported by the H-Foundation Multi-PI Basic Science Synergy Award made possible by a gift from the H Foundation to the Robert H. Lurie Comprehensive Cancer Center. A part of this work was performed by the Northwestern University ChemCore and the Developmental Therapeutics Core, which are funded by Cancer Center Support Grant P30CA060553 from the National Cancer Institute awarded to the Robert H. Lurie Comprehensive Cancer Center, and the Chicago Biomedical Consortium with support from the Searle Funds at the Chicago Community Trust. H.H. G.E.S. R.K.M. and S.A.A conceived and designed the experiments. R.K.M. designed and performed in silico screening. G.E.S. supervised the chemical aspects of these studies. H.H. conducted most of the in vitro and in vivo biological experiments. A.D.J. and J.I.-F. synthesized compounds and performed STD NMR experiments. M.I.T. performed fluorescence polarization assay and in vitro kinase assay. H.M. helped in western blot experiments. J.F.A. performed immune cells flow cytometry analysis. K.U. performed organoid culture experiment. B.L. V.S. Y.L. Y.R. R.V. Y.A.Y. and I.K. assisted in biological studies and data analysis. Z.R.C. analyzed RNA-seq data. J.B.P. and D.C. contributed to data interpretation. S.A.A. supervised the overall project. H.H. S.A.A. M.I.T. G.E.S. and A.D.J. wrote the manuscript, with input from all the other authors. H.H. A.D.J. J.I. R.K.M. G.E.S. and S.A.A. are co-inventors on patent applications covering the methods and assays to identify and characterize MYC inhibitors and derivatives. All other authors declare no competing interests. Funding Information: We thank Dr. Edward V. Prochownik for constructs and compound JKY-2-169, Dr. Shideng Bao for MYC mutant constructs, Dr. Chi V. Dang for P493-6 B cells, and Dr. John M. Sedivy for Rat-1 fibroblast cells. We thank the NUseq and the Robert H. Lurie Comprehensive Cancer Center Flow Cytometry cores of Northwestern University. We thank Dr. Andrew Mazar and Dr. Nicolette Zielinski for helpful discussions on the project design and Lisa Hurley for the technical assistance. This work was supported by grants from the National Cancer Institute : R01CA123484 , RO1CA196270 , and P50CA180995 ; and by the NewCures Biomedical Accelerator of Northwestern University . Part of the work was supported by the H-Foundation Multi-PI Basic Science Synergy Award made possible by a gift from the H Foundation to the Robert H. Lurie Comprehensive Cancer Center. A part of this work was performed by the Northwestern University ChemCore and the Developmental Therapeutics Core, which are funded by Cancer Center Support Grant P30CA060553 from the National Cancer Institute awarded to the Robert H. Lurie Comprehensive Cancer Center, and the Chicago Biomedical Consortium with support from the Searle Funds at the Chicago Community Trust. Publisher Copyright: © 2019 Elsevier Inc.

PY - 2019/11/11

Y1 - 2019/11/11

N2 - Small molecules that directly target MYC and are also well tolerated in vivo will provide invaluable chemical probes and potential anti-cancer therapeutic agents. We developed a series of small-molecule MYC inhibitors that engage MYC inside cells, disrupt MYC/MAX dimers, and impair MYC-driven gene expression. The compounds enhance MYC phosphorylation on threonine-58, consequently increasing proteasome-mediated MYC degradation. The initial lead, MYC inhibitor 361 (MYCi361), suppressed in vivo tumor growth in mice, increased tumor immune cell infiltration, upregulated PD-L1 on tumors, and sensitized tumors to anti-PD1 immunotherapy. However, 361 demonstrated a narrow therapeutic index. An improved analog, MYCi975 showed better tolerability. These findings suggest the potential of small-molecule MYC inhibitors as chemical probes and possible anti-cancer therapeutic agents.

AB - Small molecules that directly target MYC and are also well tolerated in vivo will provide invaluable chemical probes and potential anti-cancer therapeutic agents. We developed a series of small-molecule MYC inhibitors that engage MYC inside cells, disrupt MYC/MAX dimers, and impair MYC-driven gene expression. The compounds enhance MYC phosphorylation on threonine-58, consequently increasing proteasome-mediated MYC degradation. The initial lead, MYC inhibitor 361 (MYCi361), suppressed in vivo tumor growth in mice, increased tumor immune cell infiltration, upregulated PD-L1 on tumors, and sensitized tumors to anti-PD1 immunotherapy. However, 361 demonstrated a narrow therapeutic index. An improved analog, MYCi975 showed better tolerability. These findings suggest the potential of small-molecule MYC inhibitors as chemical probes and possible anti-cancer therapeutic agents.

KW - MYC

KW - MYC degradation

KW - MYC-threonine 58 phosphorylation

KW - PD-L1

KW - anti-PD1

KW - cancer therapy

KW - immunotherapy

KW - in silico screen

KW - small molecules

KW - target engagement

UR - http://www.scopus.com/inward/record.url?scp=85074430408&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85074430408&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2019.10.001

DO - 10.1016/j.ccell.2019.10.001

M3 - Article

C2 - 31679823

AN - SCOPUS:85074430408

SN - 1535-6108

VL - 36

SP - 483-497.e15

JO - Cancer cell

JF - Cancer cell

IS - 5

ER -

Small-Molecule MYC Inhibitors Suppress Tumor Growth and Enhance Immunotherapy

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this