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1.
Biochemistry ; 62(7): 1321-1329, 2023 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-36883372

RESUMO

The Myb transcription factor is involved in the proliferation of hematopoietic cells, and deregulation of its expression can lead to cancers such as leukemia. Myb interacts with various proteins, including the histone acetyltransferases p300 and CBP. Myb binds to a small domain of p300, the KIX domain (p300KIX), and inhibiting this interaction is a potential new drug discovery strategy in oncology. The available structures show that Myb binds to a very shallow pocket of the KIX domain, indicating that it might be challenging to identify inhibitors of this interaction. Here, we report the design of Myb-derived peptides which interact with p300KIX. We show that by mutating only two Myb residues that bind in or near a hotspot at the surface of p300KIX, it is possible to obtain single-digit nanomolar peptidic inhibitors of the Myb/p300KIX interaction that bind 400-fold tighter to p300KIX than wildtype Myb. These findings suggest that it might also be possible to design potent low molecular-weight compounds to disrupt the Myb/p300KIX interaction.


Assuntos
Proteína p300 Associada a E1A , Peptídeos , Proteínas Proto-Oncogênicas c-myb , Peptídeos/farmacologia , Ligação Proteica , Proteínas Proto-Oncogênicas c-myb/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-myb/química , Proteína p300 Associada a E1A/antagonistas & inibidores , Proteína p300 Associada a E1A/química
2.
Bioorg Med Chem Lett ; 22(5): 1860-3, 2012 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-22335894

RESUMO

Aromatase inhibition is the new standard of care for estrogen receptor positive breast cancer and has also potential for treatment of other diseases such as endometriosis. Simple and readily available 3-pyridyl arylethers and 1-aryl pyrrolo[2,3-c]pyridines recapitulating the key pharmacophore elements of Letrozole (1) are described and their structure-activity relationships are discussed. Potent and ligand efficient leads such as compound 23 (IC(50)=59nM on aromatase) have been identified.


Assuntos
Inibidores da Aromatase/química , Inibidores da Aromatase/farmacologia , Aromatase/metabolismo , Neoplasias da Mama/enzimologia , Piridinas/química , Piridinas/farmacologia , Pirróis/química , Pirróis/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos , Modelos Moleculares , Relação Estrutura-Atividade
3.
Cancer Chemother Pharmacol ; 62(6): 1045-54, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18301895

RESUMO

INTRODUCTION: Patupilone is a microtubule stabilizer (MTS) currently in clinical development. Here, we evaluate the anti-cancer activity in vitro and in vivo in comparison to paclitaxel and describe the pharmacokinetics (PK) of patupilone in tumor-bearing nude mice and rats. METHODS: The potency in vitro of patupilone and two other MTS, paclitaxel and ixabepilone, was determined using human colon carcinoma cell lines with low (HCT-116, HT-29, RKO) and high (HCT-15) P-glycoprotein expression (P-gp), as well as two multi-drug resistance (MDR) model cell pairs, MCF7/ADR and KB-8511 cells and their respective drug-sensitive parental counterparts. The PK of patupilone was investigated in nude mice bearing HCT-15 or HT-29 xenografts and in rats bearing s.c. pancreatic CA20498 tumors or A15 glioma tumors. Anti-cancer activity in vivo was compared to that of paclitaxel using three different human tumor colon models. The retention and efficacy of patupilone was compared in small and large HT-29 xenografts whose vascularity was determined by non-invasive magnetic resonance imaging. RESULTS: Patupilone was highly potent in vitro against four different colon carcinoma cell lines including those showing multi-drug-resistance. In contrast, paclitaxel and ixabepilone displayed significantly reduced activity with markedly increased resistance factors. In both rats and mice, a single i.v. bolus injection of patupilone (1.5-4 mg/kg) rapidly distributed from plasma to all tissues and was slowly eliminated from muscle, liver and small intestine, but showed longer retention in tumor and brain with no apparent elimination over 24 h. Patupilone showed significant activity against three human colon tumor models in vivo, unlike paclitaxel, which only had activity against low P-gp expressing tumors. In HT-29 tumors, patupilone activity and retention were independent of tumor size, blood volume and flow. CONCLUSIONS: The high potency of patupilone, which is not affected by P-gp expression either in vitro or in vivo, and favorable PK, independent of tumor vascularity, suggest that it should show significant activity in colorectal cancer and in other indications where high P-gp expression may compromise taxane activity.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma/tratamento farmacológico , Neoplasias do Colo/tratamento farmacológico , Epotilonas/uso terapêutico , Microtúbulos/efeitos dos fármacos , Neoplasias Pancreáticas/tratamento farmacológico , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinoma/irrigação sanguínea , Carcinoma/metabolismo , Carcinoma/patologia , Linhagem Celular Tumoral/efeitos dos fármacos , Linhagem Celular Tumoral/metabolismo , Neoplasias do Colo/irrigação sanguínea , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Epotilonas/farmacocinética , Epotilonas/farmacologia , Feminino , Glioma/tratamento farmacológico , Glioma/metabolismo , Glioma/patologia , Imageamento por Ressonância Magnética , Camundongos , Camundongos Nus , Proteínas de Neoplasias/metabolismo , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Ratos , Ratos Endogâmicos Lew , Distribuição Tecidual , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Acta Crystallogr D Biol Crystallogr ; 63(Pt 1): 80-93, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17164530

RESUMO

Chronic myelogenous leukaemia (CML) results from the Bcr-Abl oncoprotein, which has a constitutively activated Abl tyrosine kinase domain. Although most chronic phase CML patients treated with imatinib as first-line therapy maintain excellent durable responses, patients who have progressed to advanced-stage CML frequently fail to respond or lose their response to therapy owing to the emergence of drug-resistant mutants of the protein. More than 40 such point mutations have been observed in imatinib-resistant patients. The crystal structures of wild-type and mutant Abl kinase in complex with imatinib and other small-molecule Abl inhibitors were determined, with the aim of understanding the molecular basis of resistance and to aid in the design and optimization of inhibitors active against the resistance mutants. These results are presented in a way which illustrates the approaches used to generate multiple structures, the type of information that can be gained and the way that this information is used to support drug discovery.


Assuntos
Antineoplásicos/farmacologia , Química Farmacêutica/métodos , Desenho de Fármacos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Animais , Sítios de Ligação , Cristalização , Cristalografia por Raios X , Indústria Farmacêutica/métodos , Humanos , Modelos Químicos , Modelos Genéticos , Modelos Moleculares , Conformação Molecular , Mutação Puntual
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