Enhancing intracellular accumulation and target engagement of PROTACs with reversible covalent chemistry

Wen Hao Guo; Xiaoli Qi; Xin Yu; Yang Liu; Chan I. Chung; Fang Bai; Xingcheng Lin; Dong Lu; Lingfei Wang; Jianwei Chen; Lynn Hsiao Su; Krystle J. Nomie; Feng Li; Meng C. Wang; Xiaokun Shu; José N. Onuchic; Jennifer A. Woyach; Michael L. Wang; Jin Wang

doi:10.1038/s41467-020-17997-6

Enhancing intracellular accumulation and target engagement of PROTACs with reversible covalent chemistry

Wen Hao Guo, Xiaoli Qi, Xin Yu, Yang Liu, Chan I. Chung, Fang Bai, Xingcheng Lin, Dong Lu, Lingfei Wang, Jianwei Chen, Lynn Hsiao Su, Krystle J. Nomie, Feng Li, Meng C. Wang, Xiaokun Shu, José N. Onuchic, Jennifer A. Woyach, Michael L. Wang, Jin Wang

Lymphoma-Myeloma

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

112 Scopus citations

Abstract

Current efforts in the proteolysis targeting chimera (PROTAC) field mostly focus on choosing an appropriate E3 ligase for the target protein, improving the binding affinities towards the target protein and the E3 ligase, and optimizing the PROTAC linker. However, due to the large molecular weights of PROTACs, their cellular uptake remains an issue. Through comparing how different warhead chemistry, reversible noncovalent (RNC), reversible covalent (RC), and irreversible covalent (IRC) binders, affects the degradation of Bruton’s Tyrosine Kinase (BTK), we serendipitously discover that cyano-acrylamide-based reversible covalent chemistry can significantly enhance the intracellular accumulation and target engagement of PROTACs and develop RC-1 as a reversible covalent BTK PROTAC with a high target occupancy as its corresponding kinase inhibitor and effectiveness as a dual functional inhibitor and degrader, a different mechanism-of-action for PROTACs. Importantly, this reversible covalent strategy is generalizable to improve other PROTACs, opening a path to enhance PROTAC efficacy.

Original language	English (US)
Article number	4268
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-17997-6
State	Published - Dec 1 2020

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

Access to Document

10.1038/s41467-020-17997-6

Cite this

Guo, W. H., Qi, X., Yu, X., Liu, Y., Chung, C. I., Bai, F., Lin, X., Lu, D., Wang, L., Chen, J., Su, L. H., Nomie, K. J., Li, F., Wang, M. C., Shu, X., Onuchic, J. N., Woyach, J. A., Wang, M. L., & Wang, J. (2020). Enhancing intracellular accumulation and target engagement of PROTACs with reversible covalent chemistry. Nature communications, 11(1), Article 4268. https://doi.org/10.1038/s41467-020-17997-6

Guo, WH, Qi, X, Yu, X, Liu, Y, Chung, CI, Bai, F, Lin, X, Lu, D, Wang, L, Chen, J, Su, LH, Nomie, KJ, Li, F, Wang, MC, Shu, X, Onuchic, JN, Woyach, JA, Wang, ML & Wang, J 2020, 'Enhancing intracellular accumulation and target engagement of PROTACs with reversible covalent chemistry', Nature communications, vol. 11, no. 1, 4268. https://doi.org/10.1038/s41467-020-17997-6

@article{3464a60925984b739e4d74cb3fe913b3,

title = "Enhancing intracellular accumulation and target engagement of PROTACs with reversible covalent chemistry",

abstract = "Current efforts in the proteolysis targeting chimera (PROTAC) field mostly focus on choosing an appropriate E3 ligase for the target protein, improving the binding affinities towards the target protein and the E3 ligase, and optimizing the PROTAC linker. However, due to the large molecular weights of PROTACs, their cellular uptake remains an issue. Through comparing how different warhead chemistry, reversible noncovalent (RNC), reversible covalent (RC), and irreversible covalent (IRC) binders, affects the degradation of Bruton{\textquoteright}s Tyrosine Kinase (BTK), we serendipitously discover that cyano-acrylamide-based reversible covalent chemistry can significantly enhance the intracellular accumulation and target engagement of PROTACs and develop RC-1 as a reversible covalent BTK PROTAC with a high target occupancy as its corresponding kinase inhibitor and effectiveness as a dual functional inhibitor and degrader, a different mechanism-of-action for PROTACs. Importantly, this reversible covalent strategy is generalizable to improve other PROTACs, opening a path to enhance PROTAC efficacy.",

author = "Guo, {Wen Hao} and Xiaoli Qi and Xin Yu and Yang Liu and Chung, {Chan I.} and Fang Bai and Xingcheng Lin and Dong Lu and Lingfei Wang and Jianwei Chen and Su, {Lynn Hsiao} and Nomie, {Krystle J.} and Feng Li and Wang, {Meng C.} and Xiaokun Shu and Onuchic, {Jos{\'e} N.} and Woyach, {Jennifer A.} and Wang, {Michael L.} and Jin Wang",

note = "Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = dec,

day = "1",

doi = "10.1038/s41467-020-17997-6",

language = "English (US)",

volume = "11",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

TY - JOUR

T1 - Enhancing intracellular accumulation and target engagement of PROTACs with reversible covalent chemistry

AU - Guo, Wen Hao

AU - Qi, Xiaoli

AU - Yu, Xin

AU - Liu, Yang

AU - Chung, Chan I.

AU - Bai, Fang

AU - Lin, Xingcheng

AU - Lu, Dong

AU - Wang, Lingfei

AU - Chen, Jianwei

AU - Su, Lynn Hsiao

AU - Nomie, Krystle J.

AU - Li, Feng

AU - Wang, Meng C.

AU - Shu, Xiaokun

AU - Onuchic, José N.

AU - Woyach, Jennifer A.

AU - Wang, Michael L.

AU - Wang, Jin

PY - 2020/12/1

Y1 - 2020/12/1

N2 - Current efforts in the proteolysis targeting chimera (PROTAC) field mostly focus on choosing an appropriate E3 ligase for the target protein, improving the binding affinities towards the target protein and the E3 ligase, and optimizing the PROTAC linker. However, due to the large molecular weights of PROTACs, their cellular uptake remains an issue. Through comparing how different warhead chemistry, reversible noncovalent (RNC), reversible covalent (RC), and irreversible covalent (IRC) binders, affects the degradation of Bruton’s Tyrosine Kinase (BTK), we serendipitously discover that cyano-acrylamide-based reversible covalent chemistry can significantly enhance the intracellular accumulation and target engagement of PROTACs and develop RC-1 as a reversible covalent BTK PROTAC with a high target occupancy as its corresponding kinase inhibitor and effectiveness as a dual functional inhibitor and degrader, a different mechanism-of-action for PROTACs. Importantly, this reversible covalent strategy is generalizable to improve other PROTACs, opening a path to enhance PROTAC efficacy.

AB - Current efforts in the proteolysis targeting chimera (PROTAC) field mostly focus on choosing an appropriate E3 ligase for the target protein, improving the binding affinities towards the target protein and the E3 ligase, and optimizing the PROTAC linker. However, due to the large molecular weights of PROTACs, their cellular uptake remains an issue. Through comparing how different warhead chemistry, reversible noncovalent (RNC), reversible covalent (RC), and irreversible covalent (IRC) binders, affects the degradation of Bruton’s Tyrosine Kinase (BTK), we serendipitously discover that cyano-acrylamide-based reversible covalent chemistry can significantly enhance the intracellular accumulation and target engagement of PROTACs and develop RC-1 as a reversible covalent BTK PROTAC with a high target occupancy as its corresponding kinase inhibitor and effectiveness as a dual functional inhibitor and degrader, a different mechanism-of-action for PROTACs. Importantly, this reversible covalent strategy is generalizable to improve other PROTACs, opening a path to enhance PROTAC efficacy.

UR - http://www.scopus.com/inward/record.url?scp=85089886712&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85089886712&partnerID=8YFLogxK

U2 - 10.1038/s41467-020-17997-6

DO - 10.1038/s41467-020-17997-6

M3 - Article

C2 - 32848159

AN - SCOPUS:85089886712

SN - 2041-1723

VL - 11

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 4268

ER -

Enhancing intracellular accumulation and target engagement of PROTACs with reversible covalent chemistry

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this