Peptide-based covalent inhibitors of MALT1 paracaspase

John M. Hatcher; Guangyan Du; Lorena Fontán; Ilkay Us; Qi Qiao; Spandan Chennamadhavuni; Jay Shao; Hao Wu; Ari Melnick; Nathanael S. Gray; David A. Scott

doi:10.1016/j.bmcl.2019.03.046

Peptide-based covalent inhibitors of MALT1 paracaspase

John M. Hatcher, Guangyan Du, Lorena Fontán, Ilkay Us, Qi Qiao, Spandan Chennamadhavuni, Jay Shao, Hao Wu, Ari Melnick, Nathanael S. Gray, David A. Scott

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

13 Scopus citations

Abstract

Potent and selective substrate-based covalent inhibitors of MALT1 protease were developed from the tetrapeptide tool compound Z-VRPR-fmk. To improve cell permeability, we replaced one arginine residue. We further optimized a series of tripeptides and identified compounds that were potent in both a GloSensor reporter assay measuring cellular MALT1 protease activity, and an OCI-Ly3 cell proliferation assay. Example compounds showed good overall selectivity towards cysteine proteases, and one compound was selected for further profiling in ABL-DLBCL cells and xenograft efficacy models.

Original language	English (US)
Pages (from-to)	1336-1339
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	29
Issue number	11
DOIs	https://doi.org/10.1016/j.bmcl.2019.03.046
State	Published - Jun 1 2019
Externally published	Yes

Keywords

Covalent
Inhibitors
Peptide
Protease

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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10.1016/j.bmcl.2019.03.046

Cite this

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abstract = "Potent and selective substrate-based covalent inhibitors of MALT1 protease were developed from the tetrapeptide tool compound Z-VRPR-fmk. To improve cell permeability, we replaced one arginine residue. We further optimized a series of tripeptides and identified compounds that were potent in both a GloSensor reporter assay measuring cellular MALT1 protease activity, and an OCI-Ly3 cell proliferation assay. Example compounds showed good overall selectivity towards cysteine proteases, and one compound was selected for further profiling in ABL-DLBCL cells and xenograft efficacy models.",

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T1 - Peptide-based covalent inhibitors of MALT1 paracaspase

AU - Hatcher, John M.

AU - Du, Guangyan

AU - Fontán, Lorena

AU - Us, Ilkay

AU - Qiao, Qi

AU - Chennamadhavuni, Spandan

AU - Shao, Jay

AU - Wu, Hao

AU - Melnick, Ari

AU - Gray, Nathanael S.

AU - Scott, David A.

PY - 2019/6/1

Y1 - 2019/6/1

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AB - Potent and selective substrate-based covalent inhibitors of MALT1 protease were developed from the tetrapeptide tool compound Z-VRPR-fmk. To improve cell permeability, we replaced one arginine residue. We further optimized a series of tripeptides and identified compounds that were potent in both a GloSensor reporter assay measuring cellular MALT1 protease activity, and an OCI-Ly3 cell proliferation assay. Example compounds showed good overall selectivity towards cysteine proteases, and one compound was selected for further profiling in ABL-DLBCL cells and xenograft efficacy models.

KW - Covalent

KW - Inhibitors

KW - Peptide

KW - Protease

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Peptide-based covalent inhibitors of MALT1 paracaspase

Abstract

Keywords

ASJC Scopus subject areas

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