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1.
Anal Biochem ; 548: 44-52, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29444450

RESUMO

K-RAS is mutated in approximately 30% of human cancers, resulting in increased RAS signaling and tumor growth. Thus, RAS is a highly validated therapeutic target, especially in tumors of the pancreas, lung and colon. Although directly targeting RAS has proven to be challenging, it may be possible to target other proteins involved in RAS signaling, such as the guanine nucleotide exchange factor Son of Sevenless (SOS). We have previously reported on the discovery of small molecules that bind to SOS1, activate SOS-mediated nucleotide exchange on RAS, and paradoxically inhibit ERK phosphorylation (Burns et al., PNAS, 2014). Here, we describe the discovery of additional, structurally diverse small molecules that also bind to SOS1 in the same pocket and elicit similar biological effects. We tested >160,000 compounds in a fluorescence-based assay to assess their effects on SOS-mediated nucleotide exchange. X-Ray structures revealed that these small molecules bind to the CDC25 domain of SOS1. Compounds that elicited high levels of nucleotide exchange activity in vitro increased RAS-GTP levels in cells, and inhibited phospho ERK levels at higher treatment concentrations. The identification of structurally diverse SOS1 binding ligands may assist in the discovery of new molecules designed to target RAS-driven tumors.


Assuntos
Sistema de Sinalização das MAP Quinases , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Proteína SOS1/metabolismo , Células HeLa , Humanos , Proteínas Proto-Oncogênicas p21(ras)/química , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteína SOS1/química , Proteína SOS1/genética
2.
J Med Chem ; 65(21): 14614-14629, 2022 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-36300829

RESUMO

Activating mutations in KRAS are the most frequent oncogenic alterations in cancer. The oncogenic hotspot position 12, located at the lip of the switch II pocket, offers a covalent attachment point for KRASG12C inhibitors. To date, KRASG12C inhibitors have been discovered by first covalently binding to the cysteine at position 12 and then optimizing pocket binding. We report on the discovery of the in vivo active KRASG12C inhibitor BI-0474 using a different approach, in which small molecules that bind reversibly to the switch II pocket were identified and then optimized for non-covalent binding using structure-based design. Finally, the Michael acceptor containing warhead was attached. Our approach offers not only an alternative approach to discovering KRASG12C inhibitors but also provides a starting point for the discovery of inhibitors against other oncogenic KRAS mutants.


Assuntos
Neoplasias , Proteínas Proto-Oncogênicas p21(ras) , Humanos , Proteínas Proto-Oncogênicas p21(ras)/genética , Genes ras , Mutação , Neoplasias/genética , Cisteína
3.
ACS Med Chem Lett ; 9(9): 941-946, 2018 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-30258545

RESUMO

Proteins in the RAS family are important regulators of cellular signaling and, when mutated, can drive cancer pathogenesis. Despite considerable effort over the last 30 years, RAS proteins have proven to be recalcitrant therapeutic targets. One approach for modulating RAS signaling is to target proteins that interact with RAS, such as the guanine nucleotide exchange factor (GEF) son of sevenless homologue 1 (SOS1). Here, we report hit-to-lead studies on quinazoline-containing compounds that bind to SOS1 and activate nucleotide exchange on RAS. Using structure-based design, we refined the substituents attached to the quinazoline nucleus and built in additional interactions not present in the initial HTS hit. Optimized compounds activate nucleotide exchange at single-digit micromolar concentrations in vitro. In HeLa cells, these quinazolines increase the levels of RAS-GTP and cause signaling changes in the mitogen-activated protein kinase/extracellular regulated kinase (MAPK/ERK) pathway.

4.
J Med Chem ; 61(14): 6002-6017, 2018 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-29856609

RESUMO

Deregulated RAS activity, often the result of mutation, is implicated in approximately 30% of all human cancers. Despite this statistic, no clinically successful treatment for RAS-driven tumors has yet been developed. One approach for modulating RAS activity is to target and affect the activity of proteins that interact with RAS, such as the guanine nucleotide exchange factor (GEF) son of sevenless homologue 1 (SOS1). Here, we report on structure-activity relationships (SAR) in an indole series of compounds. Using structure-based design, we systematically explored substitution patterns on the indole nucleus, the pendant amino acid moiety, and the linker unit that connects these two fragments. Best-in-class compounds activate the nucleotide exchange process at submicromolar concentrations in vitro, increase levels of active RAS-GTP in HeLa cells, and elicit signaling changes in the mitogen-activated protein kinase-extracellular regulated kinase (MAPK-ERK) pathway, resulting in a decrease in pERK1/2T202/Y204 protein levels at higher compound concentrations.


Assuntos
Desenho de Fármacos , Indóis/química , Indóis/farmacologia , Piperidinas/química , Proteína SOS1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas ras/metabolismo , Células HeLa , Humanos , Modelos Moleculares , Conformação Proteica , Proteína SOS1/química , Relação Estrutura-Atividade , Proteínas ras/química
5.
J Med Chem ; 61(19): 8875-8894, 2018 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-30205005

RESUMO

Son of sevenless homologue 1 (SOS1) is a guanine nucleotide exchange factor that catalyzes the exchange of GDP for GTP on RAS. In its active form, GTP-bound RAS is responsible for numerous critical cellular processes. Aberrant RAS activity is involved in ∼30% of all human cancers; hence, SOS1 is an attractive therapeutic target for its role in modulating RAS activation. Here, we describe a new series of benzimidazole-derived SOS1 agonists. Using structure-guided design, we discovered small molecules that increase nucleotide exchange on RAS in vitro at submicromolar concentrations, bind to SOS1 with low double-digit nanomolar affinity, rapidly enhance cellular RAS-GTP levels, and invoke biphasic signaling changes in phosphorylation of ERK 1/2. These compounds represent the most potent series of SOS1 agonists reported to date.


Assuntos
Benzimidazóis/farmacologia , Descoberta de Drogas/normas , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Proteína SOS1/agonistas , Proteína SOS1/metabolismo , Benzimidazóis/química , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fatores de Troca do Nucleotídeo Guanina/química , Guanosina Difosfato/metabolismo , Guanosina Trifosfato/metabolismo , Células HeLa , Humanos , Fosforilação , Conformação Proteica , Proteínas Proto-Oncogênicas p21(ras)/química , Relação Estrutura-Atividade
6.
Org Lett ; 15(1): 62-4, 2013 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-23249392

RESUMO

A stereoselective synthesis of a fully protected version of the disaccharide unit (2) of incednine (1) is described. The synthesis of 2 proceeds in 4.7% overall yield from commercially available allyl α-d-galactopyranoside over the longest linear sequence.


Assuntos
Dissacarídeos/síntese química , Galactose/química , Lactamas/síntese química , Dissacarídeos/química , Glicosilação , Lactamas/química , Estrutura Molecular , Estereoisomerismo
7.
Org Lett ; 13(10): 2734-7, 2011 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-21510632

RESUMO

A highly stereoselective synthesis of a model C(18)-C(35) spiroketal unit (7) of integramycin has been accomplished via an enantioselective stannyl-crotylboration reaction and an N-iodosuccinimide-mediated spiroketalization of 19a.


Assuntos
Furanos/química , Modelos Moleculares , Naftalenos/química , Compostos de Espiro/síntese química , Estrutura Molecular , Compostos de Espiro/química , Estereoisomerismo
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