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Chemical methodology as a source of small-molecule checkpoint inhibitors and heat shock protein 70 (Hsp70) modulators

Huryn, DM and Brodsky, JL and Brummond, KM and Chambers, PG and Eyer, B and Ireland, AW and Kawasumi, M and LaPorte, MG and Lloyd, K and Manteau, B and Nghiem, P and Quade, B and Seguin, SP and Wipf, P (2011) Chemical methodology as a source of small-molecule checkpoint inhibitors and heat shock protein 70 (Hsp70) modulators. Proceedings of the National Academy of Sciences of the United States of America, 108 (17). 6757 - 6762. ISSN 0027-8424

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Abstract

Unique chemical methodology enables the synthesis of innovative and diverse scaffolds and chemotypes and allows access to previously unexplored "chemical space." Compound collections based on such new synthetic methods can provide small-molecule probes of proteins and/or pathways whose functions are not fully understood. We describe the identification, characterization, and evolution of two such probes. In one example, a pathway-based screen for DNA damage checkpoint inhibitors identified a compound, MARPIN (ATM and ATR pathway inhibitor) that sensitizes p53-deficient cells to DNA-damaging agents. Modification of the small molecule and generation of an immobilized probe were used to selectively bind putative protein target(s) responsible for the observed activity. The second example describes a focused library approach that relied on tandem multicomponent reaction methodologies to afford a series of modulators of the heat shock protein 70 (Hsp70) molecular chaperone. The synthesis of libraries based on the structure of MAL3-101 generated a collection of chemotypes, each modulating Hsp70 function, but exhibiting divergent pharmacological activities. For example, probes that compromise the replication of a disease-associated polyomavirus were identified. These projects highlight the importance of chemical methodology development as a source of small-molecule probes and as a drug discovery starting point.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Huryn, DMhuryn@pitt.eduHURYN
Brodsky, JLjbrodsky@pitt.eduJBRODSKY0000-0002-6984-8486
Brummond, KMkbrummon@pitt.eduKBRUMMON
Chambers, PG
Eyer, B
Ireland, AW
Kawasumi, M
LaPorte, MG
Lloyd, K
Manteau, B
Nghiem, P
Quade, B
Seguin, SP
Wipf, Ppwipf@pitt.eduPWIPF
Date: 26 April 2011
Date Type: Publication
Journal or Publication Title: Proceedings of the National Academy of Sciences of the United States of America
Volume: 108
Number: 17
Page Range: 6757 - 6762
DOI or Unique Handle: 10.1073/pnas.1015251108
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Refereed: Yes
ISSN: 0027-8424
MeSH Headings: Cell Cycle Proteins--metabolism; Cell Line; DNA-Binding Proteins--metabolism; Drug Design; HSP70 Heat-Shock Proteins--antagonists & inhibitors; HSP70 Heat-Shock Proteins--metabolism; Humans; Molecular Probes--chemical synthesis; Molecular Probes--chemistry; Molecular Probes--pharmacology; Polyomavirus--physiology; Polyomavirus Infections--drug therapy; Polyomavirus Infections--metabolism; Protein-Serine-Threonine Kinases--metabolism; Signal Transduction--drug effects; Tumor Suppressor Proteins--metabolism; Virus Replication--drug effects
Other ID: NLM PMC3084104
PubMed Central ID: PMC3084104
PubMed ID: 21502524
Date Deposited: 28 May 2013 15:20
Last Modified: 02 Feb 2019 15:57
URI: http://d-scholarship.pitt.edu/id/eprint/18747

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