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

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295 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
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 - 11 Nov 2019
Externally published	Yes

Keywords

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

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10.1016/j.ccell.2019.10.001

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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

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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 = "Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",

year = "2019",

month = nov,

day = "11",

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

language = "English",

volume = "36",

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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

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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.

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

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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

Keywords

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