{"doi":"10.1073/pnas.1015251108","title":"Chemical methodology as a source of small-molecule checkpoint inhibitors and heat shock protein 70 (Hsp70) modulators","abstract":"<jats:p>\n                    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 (AT\n                    <jats:underline>M</jats:underline>\n                    and\n                    <jats:underline>A</jats:underline>\n                    T\n                    <jats:underline>R</jats:underline>\n                    <jats:underline>p</jats:underline>\n                    athway\n                    <jats:underline>in</jats:underline>\n                    hibitor) 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.\n                  </jats:p>","journal":"Proceedings of the National Academy of Sciences","year":2011,"id":684768,"datarank":0.6496100010429497,"base_score":4.330733340286331,"endowment":4.330733340286331,"self_citation_contribution":0.6496100010429497,"citation_network_contribution":0.0,"self_endowment_contribution":0.6496100010429497,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":75,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":4,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":121777,"name":"Jeffrey L. Brodsky","orcid":"0000-0002-6984-8486","position":1,"is_corresponding":false},{"id":1788990,"name":"Kay M. Brummond","orcid":null,"position":2,"is_corresponding":false},{"id":1788991,"name":"Peter G. Chambers","orcid":null,"position":3,"is_corresponding":false},{"id":1788992,"name":"Benjamin Eyer","orcid":null,"position":4,"is_corresponding":false},{"id":1788993,"name":"Alex W. Ireland","orcid":null,"position":5,"is_corresponding":false},{"id":273422,"name":"Masaoki Kawasumi","orcid":"0000-0003-4348-7608","position":6,"is_corresponding":false},{"id":1087155,"name":"Matthew G. LaPorte","orcid":null,"position":7,"is_corresponding":false},{"id":1788994,"name":"Kayla Lloyd","orcid":null,"position":8,"is_corresponding":false},{"id":1788995,"name":"Baptiste Manteau","orcid":null,"position":9,"is_corresponding":false},{"id":287858,"name":"Paul Nghiem","orcid":"0000-0003-2784-963X","position":10,"is_corresponding":false},{"id":1788996,"name":"Bettina Quade","orcid":null,"position":11,"is_corresponding":false},{"id":1788997,"name":"Sandlin P. Seguin","orcid":null,"position":12,"is_corresponding":false},{"id":247975,"name":"Peter Wipf","orcid":"0000-0001-7693-5863","position":13,"is_corresponding":false},{"id":490502,"name":"Donna M. Huryn","orcid":"0000-0001-5542-4968","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Chemical methodology as a source of small-molecule checkpoint inhibitors and heat shock protein 70 (Hsp70) modulators","abstract":"<jats:p>\n                    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 (AT\n                    <jats:underline>M</jats:underline>\n                    and\n                    <jats:underline>A</jats:underline>\n                    T\n                    <jats:underline>R</jats:underline>\n                    <jats:underline>p</jats:underline>\n                    athway\n                    <jats:underline>in</jats:underline>\n                    hibitor) 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.\n                  </jats:p>","is_dataset_classified":null,"base_score":0.0,"endowment":0.0,"datacite_reuse_total":4,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"21502524","pmcid":"PMC3084104","openalex_id":null,"authors":[],"funders":[{"funder_name":"NIGMS NIH HHS","grant_id":"P41 GM081275","title":null},{"funder_name":"NIGMS NIH HHS","grant_id":"P50GM067082","title":null},{"funder_name":"NIDDK NIH HHS","grant_id":"P30 DK079307","title":null},{"funder_name":"NIAMS NIH HHS","grant_id":"R01 AR049832","title":null},{"funder_name":"NIDDK NIH HHS","grant_id":"DK79307","title":null},{"funder_name":"NIAMS NIH HHS","grant_id":"R01-AR049832","title":null}],"total_grants":6,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[],"oa_status":"closed","license":null,"oa_locations":[{"url":"https://pnas.org/doi/pdf/10.1073/pnas.1015251108","host_type":"publisher"}],"fields_of_study":[],"mesh_terms":["Cell Line","Humans","Polyomavirus","Polyomavirus Infections","Cell Cycle Proteins","DNA-Binding Proteins","Tumor Suppressor Proteins","Molecular Probes","Virus Replication","Signal Transduction","Drug Design","HSP70 Heat-Shock Proteins","Ataxia Telangiectasia Mutated Proteins","Protein Serine-Threonine Kinases"],"keywords":[],"sdg_mappings":[],"linked_datasets":[{"doi":"10.6084/m9.figshare.25294543.v1","title":"Additional file 1 of Small molecule inhibitor targeting the Hsp70-Bim protein–protein interaction in estrogen receptor-positive breast cancer overcomes tamoxifen resistance","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.25294543","title":"Additional file 1 of Small molecule inhibitor targeting the Hsp70-Bim protein–protein interaction in estrogen receptor-positive breast cancer overcomes tamoxifen resistance","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.25294840.v1","title":"Additional file 2 of Small molecule inhibitor targeting the Hsp70-Bim protein–protein interaction in estrogen receptor-positive breast cancer overcomes tamoxifen resistance","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.25294840","title":"Additional file 2 of Small molecule inhibitor targeting the Hsp70-Bim protein–protein interaction in estrogen receptor-positive breast cancer overcomes tamoxifen resistance","publisher":"figshare","resource_type":"JournalArticle"}],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-18T14:58:49.735374Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}