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2.
Bioorg Med Chem Lett ; 19(8): 2333-7, 2009 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-19286381

RESUMO

2,7-Diamino-thiazolo[4,5-d]pyrimidine analogues were synthesized as novel epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. Representative compounds showed potent and selective EGFR inhibitory activities and inhibited in vitro cellular proliferation in EGFR-overexpressing human tumor cells. The synthesis and preliminary biological, physical, and pharmacokinetic evaluation of these thiazolopyrimidine compounds are reported.


Assuntos
Antineoplásicos/síntese química , Receptores ErbB/antagonistas & inibidores , Inibidores de Proteínas Quinases/análogos & derivados , Inibidores de Proteínas Quinases/síntese química , Pirimidinas/síntese química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Humanos , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia
3.
ACS Med Chem Lett ; 10(11): 1518-1523, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31749904

RESUMO

Herein we report the discovery of pyrazolocarboxamides as novel, potent, and kinase selective inhibitors of receptor interacting protein 2 kinase (RIP2). Fragment based screening and design principles led to the identification of the inhibitor series, and X-ray crystallography was used to inform key structural changes. Through key substitutions about the N1 and C5 N positions on the pyrazole ring significant kinase selectivity and potency were achieved. Bridged bicyclic pyrazolocarboxamide 11 represents a selective and potent inhibitor of RIP2 and will allow for a more detailed investigation of RIP2 inhibition as a therapeutic target for autoinflammatory disorders.

4.
Mol Pharmacol ; 73(2): 338-48, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17975007

RESUMO

JNJ-28871063 is a potent and highly selective pan-ErbB kinase inhibitor from a novel aminopyrimidine oxime structural class that blocks the proliferation of epidermal growth factor receptor (EGFR; ErbB1)- and ErbB2-overexpressing cells but does not affect the growth of non-ErbB-overexpressing cells. Treatment of human cancer cells with JNJ-28871063 inhibited phosphorylation of functionally important tyrosine residues in both EGFR and ErbB2 and blocked downstream signal transduction pathways responsible for proliferation and survival. A single dose of compound reduced phosphorylation of ErbB2 receptors in tumor-bearing mice, demonstrating target suppression in vivo. Tissue distribution studies show that JNJ-28871063 crosses the blood-brain barrier and penetrates into tumors, where it is able to accumulate to higher levels than those found in the plasma. JNJ-28871063 showed oral antitumor activity in human tumor xenograft models that overexpress EGFR and ErbB2. In an intracranial ErbB2-overexpressing tumor model, JNJ-28871063 extended survival relative to untreated animals. The brain is a primary site of metastasis for EGFR-overexpressing lung cancers and ErbB2-overexpressing breast cancers. Therefore, the ability to penetrate into the brain could be an advantage over existing therapies such as trastuzumab (Herceptin) and cetuximab (Erbitux), which are antibodies and do not cross the blood-brain barrier. These results show that JNJ-28871063 is orally bioavailable, has activity against EGFR and ErbB2-dependent tumor xenografts, and can penetrate into the brain and inhibit ErbB2-overexpressing tumor growth.


Assuntos
Antineoplásicos/uso terapêutico , Barreira Hematoencefálica/efeitos dos fármacos , Neoplasias Encefálicas/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , Morfolinas/química , Morfolinas/uso terapêutico , Pirimidinas/química , Pirimidinas/uso terapêutico , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Barreira Hematoencefálica/enzimologia , Neoplasias Encefálicas/enzimologia , Linhagem Celular Tumoral , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Humanos , Camundongos , Camundongos Nus , Camundongos SCID , Morfolinas/farmacologia , Pirimidinas/farmacologia , Quinazolinas/química , Quinazolinas/farmacologia , Quinazolinas/uso terapêutico , Receptores Proteína Tirosina Quinases/metabolismo , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
7.
Bioorg Med Chem Lett ; 18(12): 3495-9, 2008 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-18508264

RESUMO

We herein disclose a novel series of 4-aminopyrimidine-5-carbaldehyde oximes that are potent and selective inhibitors of both EGFR and ErbB-2 tyrosine kinases, with IC(50) values in the nanomolar range. Structure-activity relationship (SAR) studies elucidated a critical role for the 4-amino and C-6 arylamino moieties. The X-ray co-crystal structure of EGFR with 37 was determined and validated our design rationale.


Assuntos
Antineoplásicos/farmacologia , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/química , Oximas/farmacologia , Pirimidinas/farmacologia , Receptor ErbB-2/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Sítios de Ligação/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Ligação de Hidrogênio , Concentração Inibidora 50 , Modelos Moleculares , Estrutura Molecular , Oximas/síntese química , Oximas/química , Pirimidinas/síntese química , Pirimidinas/química , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade
8.
ACS Med Chem Lett ; 9(10): 1039-1044, 2018 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-30344914

RESUMO

RIP2 kinase was recently identified as a therapeutic target for a variety of autoimmune diseases. We have reported previously a selective 4-aminoquinoline-based RIP2 inhibitor GSK583 and demonstrated its effectiveness in blocking downstream NOD2 signaling in cellular models, rodent in vivo models, and human ex vivo disease models. While this tool compound was valuable in validating the biological pathway, it suffered from activity at the hERG ion channel and a poor PK/PD profile thereby limiting progression of this analog. Herein, we detail our efforts to improve both this off-target liability as well as the PK/PD profile of this series of inhibitors through modulation of lipophilicity and strengthening hinge binding ability. These efforts have led to inhibitor 7, which possesses high binding affinity for the ATP pocket of RIP2 (IC50 = 1 nM) and inhibition of downstream cytokine production in human whole blood (IC50 = 10 nM) with reduced hERG activity (14 µM).

9.
Elife ; 72018 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-29676732

RESUMO

Potent, selective and broadly characterized small molecule modulators of protein function (chemical probes) are powerful research reagents. The pharmaceutical industry has generated many high-quality chemical probes and several of these have been made available to academia. However, probe-associated data and control compounds, such as inactive structurally related molecules and their associated data, are generally not accessible. The lack of data and guidance makes it difficult for researchers to decide which chemical tools to choose. Several pharmaceutical companies (AbbVie, Bayer, Boehringer Ingelheim, Janssen, MSD, Pfizer, and Takeda) have therefore entered into a pre-competitive collaboration to make available a large number of innovative high-quality probes, including all probe-associated data, control compounds and recommendations on use (https://openscienceprobes.sgc-frankfurt.de/). Here we describe the chemical tools and target-related knowledge that have been made available, and encourage others to join the project.


Assuntos
Sondas Moleculares/metabolismo , Farmacologia/métodos , Proteínas/metabolismo , Tecnologia Farmacêutica/métodos
10.
12.
Bioorg Med Chem ; 12(22): 5845-56, 2004 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-15498660

RESUMO

The preparation of a novel series of N-aryl CBI derivatives in which an aryl substituent could be used to predictably modulate the reactivity of the resulting CC-1065/duocarmycin alkylation subunit analogue is detailed and its extension to a unique series of N-alkenyl derivatives is reported. The N-aryl derivatives were found to be exceptionally stable and to exhibit well-defined relationships between structure (X-ray), reactivity, and cytotoxic potency. When combined with the results of past investigations, the studies define a fundamental parabolic relationship between reactivity and cytotoxic potency. The parabolic relationship establishes that compounds in the series should possess sufficient stability to reach their biological target (DNA), yet maintain sufficient reactivity to effectively alkylate DNA upon reaching the biological target. Just as importantly, it defined this optimal balance of stability and reactivity that may be used for future design of related analogues. Notably, the duocarmycin SA and yatakemycin alkylation subunit lies at this optimal stability/reactivity position, whereas the CC-1065 and duocarmycin A alkylation subunits lie progressively and significantly to the left of this optimal position (too reactive).


Assuntos
Alquilantes/química , Alquilantes/metabolismo , Sequência de Bases/genética , Cristalografia por Raios X/métodos , DNA/genética , DNA/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Duocarmicinas , Indóis/química , Indóis/metabolismo , Pirrolidinonas/química , Pirrolidinonas/metabolismo
13.
J Am Chem Soc ; 126(1): 80-1, 2004 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-14709069

RESUMO

The preparation of a novel series of N-aryl CBI derivatives is detailed in which an aryl para substituent could be used to predictably modulate the reactivity of the resulting CC-1065/duocarmycin alkylation subunit analogue (rho = 0.17). The derivatives were found to be exceptionally stable and to exhibit a well-defined relationship between reactivity and cytotoxic potency. When combined with the results of an extensive series of N-acyl CBI analogues and derivatives assembled over the past 15 years, the studies define a fundamental parabolic relationship between reactivity and cytotoxic potency.


Assuntos
Antibióticos Antineoplásicos/química , Indóis/química , Pirrolidinonas/química , Alquilação , Animais , Antibióticos Antineoplásicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Duocarmicinas , Indóis/farmacologia , Leucemia L1210/tratamento farmacológico , Camundongos , Pirrolidinonas/farmacologia , Relação Estrutura-Atividade
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