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1.
Nat Commun ; 15(1): 275, 2024 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-38177131

RESUMO

Targeted protein degradation (TPD) mediates protein level through small molecule induced redirection of E3 ligases to ubiquitinate neo-substrates and mark them for proteasomal degradation. TPD has recently emerged as a key modality in drug discovery. So far only a few ligases have been utilized for TPD. Interestingly, the workhorse ligase CRBN has been observed to be downregulated in settings of resistance to immunomodulatory inhibitory drugs (IMiDs). Here we show that the essential E3 ligase receptor DCAF1 can be harnessed for TPD utilizing a selective, non-covalent DCAF1 binder. We confirm that this binder can be functionalized into an efficient DCAF1-BRD9 PROTAC. Chemical and genetic rescue experiments validate specific degradation via the CRL4DCAF1 E3 ligase. Additionally, a dasatinib-based DCAF1 PROTAC successfully degrades cytosolic and membrane-bound tyrosine kinases. A potent and selective DCAF1-BTK-PROTAC (DBt-10) degrades BTK in cells with acquired resistance to CRBN-BTK-PROTACs while the DCAF1-BRD9 PROTAC (DBr-1) provides an alternative strategy to tackle intrinsic resistance to VHL-degrader, highlighting DCAF1-PROTACS as a promising strategy to overcome ligase mediated resistance in clinical settings.


Assuntos
Proteínas de Transporte , Quimera de Direcionamento de Proteólise , Ubiquitina-Proteína Ligases , Proteínas de Transporte/metabolismo , Proteólise , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligases/metabolismo
2.
Angiogenesis ; 13(3): 259-67, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20803239

RESUMO

EphB4 and its cognitive ligand ephrinB2 play an important role in embryonic vessel development and vascular remodeling. In addition, several reports suggest that this receptor ligand pair is also involved in pathologic vessel formation in adults including tumor angiogenesis. Eph/ephrin signaling is a complex phenomena characterized by receptor forward signaling through the tyrosine kinase of the receptor and ephrin reverse signaling through various protein-protein interaction domains and phosphorylation motifs of the ephrin ligands. Therefore, interfering with EphR/ephrin signaling by the means of targeted gene ablation, soluble receptors, dominant negative mutants or antisense molecules often does not allow to discriminate between inhibition of Eph/ephrin forward and reverse signaling. We developed a specific small molecular weight kinase inhibitor of the EphB4 kinase, NVP-BHG712, which inhibits EphB4 kinase activity in the low nanomolar range in cellular assays showed high selectivity for targeting the EphB4 kinase when profiled against other kinases in biochemical as well as in cell based assays. Furthermore, NVP-BHG712 shows excellent pharmacokinetic properties and potently inhibits EphB4 autophosphorylation in tissues after oral administration. In vivo, NVP-BHG712 inhibits VEGF driven vessel formation, while it has only little effects on VEGF receptor (VEGFR) activity in vitro or in cellular assays. The data shown here suggest a close cross talk between the VEGFR and EphR signaling during vessel formation. In addition to its established function in vascular remodeling and endothelial arterio-venous differentiation, EphB4 forward signaling appears to be an important mediator of VEGF induced angiogenesis since inhibition of EphB4 forward signaling is sufficient to inhibit VEGF induced angiogenesis.


Assuntos
Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/uso terapêutico , Neovascularização Patológica/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Receptor EphB4/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacocinética , Animais , Bioensaio , Humanos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Camundongos , Neovascularização Patológica/enzimologia , Tamanho do Órgão/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Pirazóis/química , Pirazóis/farmacocinética , Pirimidinas/química , Pirimidinas/farmacocinética , Receptor EphB4/metabolismo , Transdução de Sinais/efeitos dos fármacos , Solubilidade/efeitos dos fármacos
3.
Genes Cancer ; 1(10): 1021-32, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21779428

RESUMO

Constitutively activated mutant FLT3 has emerged as a promising target for therapy for the subpopulation of acute myeloid leukemia (AML) patients who harbor it. The small molecule inhibitor, PKC412, targets mutant FLT3 and is currently in late-stage clinical trials. However, the identification of PKC412-resistant leukemic blast cells in the bone marrow of AML patients has propelled the development of novel and structurally distinct FLT3 inhibitors that have the potential to override drug resistance and more efficiently prevent disease progression or recurrence. Here, we present the novel first-generation "type II" FLT3 inhibitors, AFG206, AFG210, and AHL196, and the second-generation "type II" derivatives and AST487 analogs, AUZ454 and ATH686. All agents potently and selectively target mutant FLT3 protein kinase activity and inhibit the proliferation of cells harboring FLT3 mutants via induction of apoptosis and cell cycle inhibition. Cross-resistance between "type I" inhibitors, PKC412 and AAE871, was demonstrated. While cross-resistance was also observed between "type I" and first-generation "type II" FLT3 inhibitors, the high potency of the second-generation "type II" inhibitors was sufficient to potently kill "type I" inhibitor-resistant mutant FLT3-expressing cells. The increased potency observed for the second-generation "type II" inhibitors was observed to be due to an improved interaction with the ATP pocket of FLT3, specifically associated with introduction of a piperazine moiety and placement of an amino group in position 2 of the pyrimidine ring. Thus, we present 2 structurally novel classes of FLT3 inhibitors characterized by high selectivity and potency toward mutant FLT3 as a molecular target. In addition, presentation of the antileukemic effects of "type II" inhibitors, such as AUZ454 and ATH686, highlights a new class of highly potent FLT3 inhibitors able to override drug resistance that less potent "type I" inhibitors and "type II" first-generation FLT3 inhibitors cannot.

4.
Bioorg Med Chem Lett ; 17(2): 358-62, 2007 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-17095212

RESUMO

A series of beta-lactam derivatives has been designed and synthesized to inhibit the chymotrypsin-like activity of the human 20S proteasome. The most potent compounds of this new structural class of beta-subunit selective 20S proteasome inhibitors exhibit IC50 values in the low-nanomolar range and show good selectivity over the trypsin-like and post-glutamyl-peptide hydrolytic activities of the enzyme.


Assuntos
Quimotripsina/antagonistas & inibidores , Inibidores de Proteassoma , Inibidores da Tripsina/síntese química , Inibidores da Tripsina/farmacologia , beta-Lactamas/síntese química , beta-Lactamas/farmacologia , Cristalografia por Raios X , Desenho de Fármacos , Humanos , Modelos Moleculares , Peptídeos/química , Relação Estrutura-Atividade
5.
J Med Chem ; 47(20): 4810-3, 2004 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-15369383
6.
Bioorg Med Chem Lett ; 12(10): 1331-4, 2002 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-11992770

RESUMO

We have identified 2-aminobenzylstatine derivatives that inhibit non-covalently the chymotrypsin-like activity of the human 20S proteasome. A structure-based optimisation approach has allowed us to improve the potency of this structural class of proteasome inhibitors from micromolar to nanomolar level. The new derivatives showed good selectivity against the trypsin-like and post-glutamyl-peptide hydrolytic activities of this enzyme.


Assuntos
Compostos de Benzil/síntese química , Quimotripsina/antagonistas & inibidores , Complexos Multienzimáticos/antagonistas & inibidores , Inibidores de Proteases/síntese química , Compostos de Benzil/farmacologia , Cisteína Endopeptidases , Desenho de Fármacos , Humanos , Cinética , Modelos Moleculares , Conformação Molecular , Inibidores de Proteases/farmacologia , Complexo de Endopeptidases do Proteassoma , Relação Estrutura-Atividade
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