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

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

376 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

@article{fe1ec431635344cd84140b60deba2596,

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

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.

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 - https://www.scopus.com/pages/publications/85074430408

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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