Sulfopin is a covalent inhibitor of Pin1 that blocks Myc-driven tumors in vivo

被引：103

作者：

Dubiella, Christian ^{[1
]}

Pinch, Benika J. ^{[2
,3
,4
]}

Koikawa, Kazuhiro ^{[5
,6
,7
]}

Zaidman, Daniel ^{[1
]}

Poon, Evon ^{[8
]}

Manz, Theresa D. ^{[2
,3
,9
]}

Nabet, Behnam ^{[2
,3
]}

He, Shuning ^{[10
]}

Resnick, Efrat ^{[1
]}

Rogel, Adi ^{[1
]}

Langer, Ellen M. ^{[11
,12
]}

Daniel, Colin J. ^{[11
,12
]}

Seo, Hyuk-Soo ^{[2
]}

Chen, Ying ^{[13
]}

Adelmant, Guillaume ^{[2
,14
,15
,16
,17
]}

Sharifzadeh, Shabnam ^{[2
,14
,15
,16
,17
]}

Ficarro, Scott B. ^{[2
,14
,15
,16
,17
]}

Jamin, Yann ^{[18
]}

da Costa, Barbara Martins ^{[8
]}

Zimmerman, Mark W. ^{[10
]}

Lian, Xiaolan ^{[5
,6
,7
]}

Kibe, Shin ^{[5
,6
,7
]}

Kozono, Shingo ^{[5
,6
,7
]}

Doctor, Zainab M. ^{[2
,3
]}

Browne, Christopher M. ^{[2
,3
,27
]}

Yang, Annan ^{[2
,19
]}

Stoler-Barak, Liat ^{[20
]}

Shah, Richa B. ^{[21
,22
]}

Vangos, Nicholas E. ^{[2
]}

Geffken, Ezekiel A. ^{[2
]}

Oren, Roni ^{[23
]}

Koide, Eriko ^{[2
,3
]}

Sidi, Samuel ^{[21
,22
]}

Shulman, Ziv ^{[20
]}

Wang, Chu ^{[13
]}

Marto, Jarrod A. ^{[2
,14
,15
,16
,17
]}

Dhe-Paganon, Sirano ^{[2
]}

Look, Thomas ^{[10
,24
]}

Zhou, Xiao Zhen ^{[5
,6
,7
]}

Lu, Kun Ping ^{[5
,6
,7
]}

Sears, Rosalie C. ^{[11
,12
,25
]}

Chesler, Louis ^{[8
]}

Gray, Nathanael S. ^{[2
,3
,26
]}

London, Nir ^{[1
]}

机构：

[1] Weizmann Inst Sci, Dept Organ Chem, Rehovot, Israel

[2] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA

[3] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA

[4] Harvard Univ, Dept Chem & Chem Biol, Dept Chem Biol, Cambridge, MA USA

[5] Harvard Med Sch, Dept Med, Div Translat Therapeut, Beth Israel Deaconess Med Ctr, Boston, MA USA

[6] Harvard Med Sch, Canc Res Inst, Beth Israel Deaconess Med Ctr, Boston, MA USA

[7] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[8] Inst Canc Res, Div Clin Studies, London, England

[9] Saarland Univ, Dept Pharmaceut & Med Chem, Saarbrucken, Germany

[10] Harvard Med Sch, Dept Pediat Oncol, Dana Farber Canc Inst, Boston, MA USA

[11] Oregon Hlth & Sci Univ, Dept Mol & Med Genet, Portland, OR USA

[12] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR USA

[13] Peking Univ, Coll Chem & Mol Engn, Beijing, Peoples R China

[14] Harvard Med Sch, Dept Oncol Pathol, Dana Farber Canc Inst, Boston, MA USA

[15] Harvard Med Sch, Blais Prote Ctr, Dana Farber Canc Inst, Boston, MA USA

[16] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA

[17] Harvard Med Sch, Boston, MA 02115 USA

[18] Inst Canc Res, Div Radiotherapy & Imaging, London, England

[19] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA USA

[20] Weizmann Inst Sci, Dept Immunol, Rehovot, Israel

[21] Icahn Sch Med Mt Sinai, Dept Med, Div Hematol & Med Oncol, Tisch Canc Inst, New York, NY USA

[22] Icahn Sch Med Mt Sinai, Dept Cell Dev & Regenerat Biol, Grad Sch Biomed Sci, New York, NY USA

[23] Weizmann Inst Sci, Dept Vet Resources, Rehovot, Israel

[24] Boston Childrens Hosp, Div Pediat Hematol Oncol, Boston, MA USA

[25] Oregon Hlth & Sci Univ, Brenden Colson Ctr Pancreat Care, Portland, OR USA

[26] Stanford Univ, Dept Chem & Syst Biol, Chem H & Stanford Canc Inst, Stanford Sch Med, Stanford, CA 94305 USA

[27] AstraZeneca, Discovery Biol, Discovery Sci, Biopharmaceut R&D, Boston, MA USA

来源：

NATURE CHEMICAL BIOLOGY | 2021年 / 17卷 / 09期

基金：

以色列科学基金会; 美国国家卫生研究院;

关键词：

PROLYL-ISOMERASE PIN1; STRUCTURE-BASED DESIGN; C-MYC; EXPRESSION; PHOSPHORYLATION; ISOMERIZATION; GENE; IDENTIFICATION; DEGRADATION; DISCOVERY;

D O I：

10.1038/s41589-021-00786-7

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The peptidyl-prolyl isomerase, Pin1, is exploited in cancer to activate oncogenes and inactivate tumor suppressors. However, despite considerable efforts, Pin1 has remained an elusive drug target. Here, we screened an electrophilic fragment library to identify covalent inhibitors targeting Pin1's active site Cys113, leading to the development of Sulfopin, a nanomolar Pin1 inhibitor. Sulfopin is highly selective, as validated by two independent chemoproteomics methods, achieves potent cellular and in vivo target engagement and phenocopies Pin1 genetic knockout. Pin1 inhibition had only a modest effect on cancer cell line viability. Nevertheless, Sulfopin induced downregulation of c-Myc target genes, reduced tumor progression and conferred survival benefit in murine and zebrafish models of MYCN-driven neuroblastoma, and in a murine model of pancreatic cancer. Our results demonstrate that Sulfopin is a chemical probe suitable for assessment of Pin1-dependent pharmacology in cells and in vivo, and that Pin1 warrants further investigation as a potential cancer drug target.

引用

页码：954 / 963

页数：10

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