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1.
Bioorg Chem ; 147: 107394, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38691906

RESUMO

Epidermal growth factor receptor (EGFR) is one of the most studied drug targets for treating non-small-cell lung cancer (NSCLC). However, there are no approved inhibitors for the C797S resistance mutation caused by the third-generation EGFR inhibitor (Osimertinib). Therefore, the development of fourth-generation EGFR inhibitors is urgent. In this study, we clarified the structure-activity relationship of several synthesized compounds as fourth-generation inhibitors against human triple (Del19/T790M/C797S) mutation. Representative compound 52 showed potent inhibitory activity against EGFRL858R/T790M/C797S with an IC50 of 0.55 nM and significantly inhibited the proliferation of the Ba/F3 cell line harboring EGFRL858R/T790M/C797S with an IC50 of 43.28 nM. Moreover, 52 demonstrated good pharmacokinetic properties and excellent in vivo efficacy. Overall, the compound 52 can be considered a promising candidate for overcoming EGFR C797S-mediated mutations.


Assuntos
Acrilamidas , Compostos de Anilina , Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Proliferação de Células , Relação Dose-Resposta a Droga , Desenho de Fármacos , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB , Neoplasias Pulmonares , Inibidores de Proteínas Quinases , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Receptores ErbB/genética , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Acrilamidas/farmacologia , Acrilamidas/química , Acrilamidas/síntese química , Relação Estrutura-Atividade , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/síntese química , Compostos de Anilina/farmacologia , Compostos de Anilina/química , Compostos de Anilina/síntese química , Compostos de Anilina/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Estrutura Molecular , Animais , Camundongos , Linhagem Celular Tumoral , Mutação , Indóis , Pirimidinas
2.
Bioorg Med Chem Lett ; 96: 129519, 2023 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-37838343

RESUMO

Acute myeloid leukemia (AML) is an aggressive cancer, which is characterized by clonal expansion of myeloid progenitors in the bone marrow and peripheral blood. FMS-like tyrosine kinase 3 (FLT3) mutations are the most frequently identified mutations, present in approximately 25-30 % AML patients, making FLT3 inhibitors a crucial treatment option for AML. In this study, we described the design, synthesis and biological evaluation of a series of 2-aminopyrimidine derivatives as potent FLT3 inhibitors. Notably, compound 15 displayed potent kinase inhibitory activities against FLT3 (FLT3-WT IC50 = 7.42 ± 1.23 nM; FLT3-D835Y IC50 = 9.21 ± 0.04 nM) and robust antiproliferative activities against MV4-11 cells (IC50 = 0.83 ± 0.15 nM) and MOLM-13 cells (IC50 = 10.55 ± 1.70 nM). Compound 15 also possessed potent antiproliferative activities against BaF3 cells carrying various FLT3-TKD and FLT3-ITD-TKD mutations, indicating its potential to overcome on-target resistance caused by FLT3 mutations. In summary, compound 15 showed promising potential for further exploration as a treatment of AML.


Assuntos
Leucemia Mieloide Aguda , Tirosina Quinase 3 Semelhante a fms , Humanos , Tirosina Quinase 3 Semelhante a fms/genética , Inibidores de Proteínas Quinases/farmacologia , Linhagem Celular Tumoral , Mutação , Leucemia Mieloide Aguda/tratamento farmacológico , Apoptose
3.
Acta Pharmacol Sin ; 43(1): 220-228, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33782542

RESUMO

Checkpoint kinase 1 inhibitors (CHK1i) have shown impressive single-agent efficacy in treatment of certain tumors, as monotherapy or potentiators of chemotherapy in clinical trials, but the sensitive tumor types and downstream effectors to dictate the therapeutic responses to CHK1i remains unclear. In this study we first analyzed GDSC (Genomics of Drug Sensitivity in Cancer) and DepMap database and disclosed that hematologic malignancies (HMs) were relatively sensitive to CHK1i or CHK1 knockdown. This notion was confirmed by examining PY34, a new and potent in-house selective CHK1i, which exhibited potent anti-HM effect in vitro and in vivo, as single agent. We demonstrated that the downregulation of c-Myc and its signaling pathway was the common transcriptomic profiling response of sensitive HM cell lines to PY34, whereas overexpressing c-Myc could partially rescue the anticancer effect of PY34. Strikingly, we revealed the significant correlations between downregulation of c-Myc and cell sensitivity to PY34 in 17 HM cell lines and 39 patient-derived cell (PDC) samples. Thus, our results demonstrate that HMs are more sensitive to CHK1i than solid tumors, and c-Myc downregulation could represent the CHK1i efficacy in HMs.


Assuntos
Proteínas de Ligação a DNA/antagonistas & inibidores , Regulação para Baixo/efeitos dos fármacos , Neoplasias Hematológicas/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Fatores de Transcrição/antagonistas & inibidores , Animais , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Quinase 1 do Ponto de Checagem/antagonistas & inibidores , Quinase 1 do Ponto de Checagem/deficiência , Quinase 1 do Ponto de Checagem/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Neoplasias Hematológicas/metabolismo , Neoplasias Hematológicas/patologia , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos Nus , Camundongos SCID , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
4.
J Med Chem ; 66(17): 11792-11814, 2023 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-37584545

RESUMO

FLT3 inhibitors as single agents have limited effects because of acquired and adaptive resistance and the cardiotoxicity related to human ether-a-go-go-related gene (hERG) channel blockade further impedes safe drugs to the market. Inhibitors having potential to overcome resistance and reduce hERG affinity are highly demanded. Here, we reported a dual FLT3/CHK1 inhibitor 18, which displayed potencies to overcome varying acquired resistance in BaF3 cells with FLT3-TKD and FLT3-ITD-TKD mutations. Moreover, 18 displayed high selectivity over c-KIT more than 1700-fold and greatly reduced hERG affinity, with an IC50 value of 58.4 µM. Further mechanistic studies demonstrated 18 can upregulate p53 and abolish the outgrowth of adaptive resistant cells. In the in vivo studies, 18 demonstrated favorable PK profiles and good safety, suppressed the tumor growth in the MV-4-11 cell inoculated mouse xenograft model, and prolonged the survival in the Molm-13 transplantation model, supporting its further development.


Assuntos
Antineoplásicos , Leucemia Mieloide Aguda , Humanos , Animais , Camundongos , Leucemia Mieloide Aguda/tratamento farmacológico , Linhagem Celular Tumoral , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Tirosina Quinase 3 Semelhante a fms/genética , Mutação , Apoptose , Antineoplásicos/farmacologia
5.
Leukemia ; 37(3): 539-549, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36526736

RESUMO

FLT3 inhibitors (FLT3i) are widely used for the treatment of acute myeloid leukemia (AML), but adaptive and acquired resistance remains a primary challenge. Inhibitors simultaneously blocking adaptive and acquired resistance are highly demanded. Here, we observed the potential of CHK1 inhibitors to synergistically improve the therapeutic effect of FLT3i in FLT3-mutated AML cells. Notably, the combination overcame adaptive resistance. The simultaneous targeting of FLT3 and CHK1 kinases may overcome acquired and adaptive resistance. A dual FLT3/CHK1 inhibitor 30 with a good oral PK profile was identified. Mechanistic studies indicated that 30 inhibited FLT3 and CHK1, downregulated the c-Myc pathway and further activated the p53 pathway. Functional studies showed that 30 was more selective against cells with various FLT3 mutants, overcame adaptive resistance in vitro, and effectively inhibited resistant FLT3-ITD AML in vivo. Moreover, 30 showed favorable druggability without significant blood toxicity or myelosuppression and exhibited a good oral PK profile with a T1/2 over 12 h in beagles. These findings support the targeting of FLT3 and CHK1 as a novel strategy for overcoming adaptive and acquired resistance to FLT3i therapy in AML and suggest 30 as a potential clinical candidate.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Leucemia Mieloide Aguda , Animais , Cães , Humanos , Apoptose , Linhagem Celular Tumoral , Tirosina Quinase 3 Semelhante a fms/genética , Tirosina Quinase 3 Semelhante a fms/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico
6.
Eur J Med Chem ; 243: 114732, 2022 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-36075147

RESUMO

The M2 polarized macrophages modulation has been described as a beneficial approach to facilitate the myelin repairing and inflammation microenvironment remodeling of multiple sclerosis (MS). Whereas, the M2 polarization involves complex mechanisms, and the modulators are still limited. As a protein kinase B (Akt) inhibitor, compound 2 was found promoting M2 polarization activity in our previous research, here we report the identification of a new modulator B9 with high M2-marker Arg1 upregulation activity, M1 polarization inhibition and ablated Akt1 inhibition activities. B9 has promising pharmacokinetic profiles, and significantly ameliorates the symptom and reduces demyelination in EAE mice. Moreover, the inflammation microenvironment is remodeled after B9 administration, with promoted M2-type macrophages and inhibited M1 polarization in the CNS and periphery, and suppressed the proinflammatory Th1 and Th17 cells responses. Therefore, the new macrophage M2 polarization modulator B9 could present a candidate for fulfilling the therapeutic strategies of MS.


Assuntos
Esclerose Múltipla , Camundongos , Animais , Esclerose Múltipla/tratamento farmacológico , Ativação de Macrófagos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Macrófagos/metabolismo , Células Th17
7.
J Med Chem ; 65(4): 3229-3248, 2022 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-35138851

RESUMO

Herein, we report two promising compounds 30 and 36 possessing nanomolar FLT3 inhibitory activities (IC50 = 1.5-7.2 nM), high selectivity over c-KIT (>1000-fold), and excellent anti-AML activity (MV4-11 IC50 = 0.8-3.2 nM). Furthermore, these two compounds efficiently inhibited the growth of multiple mutant BaF3 cells expressing FLT3-ITD, FLT3-D835V/F, FLT3-F691L, FLT3-ITD-F691L, and FLT3-ITD-D835Y. Oral administration of 30 and 36 at 6 mg/kg/d could significantly suppress tumor growth in the MV4-11 cell-inoculated xenograft model, exhibiting tumor growth inhibitory rates of 83.5% and 95.1%, respectively. Importantly, 36 could prolong the mouse survival time in the FLT3-ITD-TKD dual mutation syngeneic mouse model (BaF3-FLT3-ITD-D835Y) at a dose of 6 mg/kg p.o. bid/4W. No clear myelosuppression was observed in the treated group of 36 in the MPO strain of zebrafish, even at 10 µM. In summary, our data demonstrated that 36 may represent a promising candidate for the treatment of FLT3 mutant AML.


Assuntos
Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-kit/antagonistas & inibidores , Pirimidinas/síntese química , Pirimidinas/farmacologia , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/patologia , Relação Dose-Resposta a Droga , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Camundongos , Camundongos Endogâmicos BALB C , Inibidores de Proteínas Quinases/toxicidade , Pirimidinas/toxicidade , Transdução de Sinais/efeitos dos fármacos , Especificidade por Substrato , Ensaios Antitumorais Modelo de Xenoenxerto , Peixe-Zebra
8.
Eur J Med Chem ; 235: 114257, 2022 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-35367710

RESUMO

Multiple myeloma (MM) is a highly malignant hematologic cancer that occurs when an atypical plasma cell develops in the bone marrow and reproduces quickly. Despite varies of new drugs have been developed or under clinic trial, MM is still essentially incurable, while XPO1 inhibition has emerged as a promising therapeutic strategy in the treatment of MM. Using the second-generation XPO1 inhibitor KPT-8602 as the lead compound, structure-based optimization provided D4 with high anti-proliferation efficacy (IC50 = 24 nM in MM.1S). In addition, the treatment with D4 significantly induced MM.1S cell cycle arrested and cell apoptosis, which was confirmed as on-target effect by immunofluorescence microscopy and competitive binding assay. Moreover, D4 displayed good metabolic stability over rat plasma and liver microsomes, as well as good pharmacokinetic profile on SD rat model with high drug exposure and decent bioavailability by oral gavage. All these good properties of D4 pave the way for further drug development and clinical application.


Assuntos
Antineoplásicos , Mieloma Múltiplo , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Hidrazinas/farmacologia , Carioferinas/metabolismo , Mieloma Múltiplo/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Receptores Citoplasmáticos e Nucleares/metabolismo , Sulfonamidas/farmacologia , Triazóis/farmacologia
9.
Future Med Chem ; 12(10): 961-981, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32314599

RESUMO

Fms-like tyrosine kinase-3 (FLT3) mutations occur in approximately 30% of acute myeloid leukemia (AML) cases, suggesting FLT3 as an attractive target for AML treatment. Early FLT3 inhibitors enhance antileukemia efficacy by inhibiting multiple targets, and thus had stronger off-target activity, increasing their toxicity. Recently, a number of potent and selective FLT3 inhibitors have been developed, many of which are effective against multiple mutations. This review outlines the evolution of AML-targeting FLT3 inhibitors by focusing on their chemotypes, selectivity and activity over FLT3 wild-type and FLT3 mutations as well as new techniques related to FLT3. Compounds that currently enter the late clinical stage or have entered the market are also briefly reported.


Assuntos
Antineoplásicos/farmacologia , Leucemia Mieloide Aguda/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Antineoplásicos/química , Humanos , Leucemia Mieloide Aguda/metabolismo , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Tirosina Quinase 3 Semelhante a fms/metabolismo
10.
Eur J Med Chem ; 173: 44-62, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30986571

RESUMO

Through virtual screening, we identified the lead compound MCL1020, which exhibited modest CHK1 inhibitory activity. Then a series of 5-(pyrimidin-2-ylamino)picolinonitrile derivatives as CHK1 inhibitors were discovered by further rational optimization. One promising molecule, (R)-17, whose potency was one of the best, had an IC50 of 0.4 nM with remarkable selectivity (>4300-fold CHK1 vs. CHK2). Compound (R)-17 effectively inhibited the growth of malignant hematopathy cell lines especially Z-138 (IC50: 0.013 µM) and displayed low affinity for hERG (IC50 > 40 µM). Moreover, (R)-17 significantly suppressed the tumor growth in Z-138 cell inoculated xenograft model (20 mg/kg I.V., TGI = 90.29%) as a single agent with body weight unaffected. Taken together, our data demonstrated compound (R)-17 could be a promising drug candidate for the treatment of hematologic malignancies.


Assuntos
Quinase 1 do Ponto de Checagem/antagonistas & inibidores , Descoberta de Drogas , Neoplasias Hematológicas/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Quinase 1 do Ponto de Checagem/metabolismo , Relação Dose-Resposta a Droga , Neoplasias Hematológicas/metabolismo , Humanos , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade
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