RESUMEN
Evading apoptosis has been linked to tumor development and chemoresistance. One mechanism for this evasion is the overexpression of prosurvival B-cell lymphoma-2 (BCL-2) family proteins, which gives cancer cells a survival advantage. Mcl-1, a member of the BCL-2 family, is among the most frequently amplified genes in cancer. Targeting myeloid cell leukemia-1 (MCL-1) protein is a successful strategy to induce apoptosis and overcome tumor resistance to chemotherapy and targeted therapy. Various strategies to inhibit the antiapoptotic activity of MCL-1 protein, including transcription, translation, and the degradation of MCL-1 protein, have been tested. Neutralizing MCL-1's function by targeting its interactions with other proteins via BCL-2 interacting mediator (BIM)S2A has been shown to be an equally effective approach. Encouraged by the design of venetoclax and its efficacy in chronic lymphocytic leukemia, scientists have developed other BCL-2 homology (BH3) mimetics-particularly MCL-1 inhibitors (MCL-1i)-that are currently in clinical trials for various cancers. While extensive reviews of MCL-1i are available, critical analyses focusing on the challenges of MCL-1i and their optimization are lacking. In this review, we discuss the current knowledge regarding clinically relevant MCL-1i and focus on predictive biomarkers of response, mechanisms of resistance, major issues associated with use of MCL-1i, and the future use of and maximization of the benefits from these agents.
RESUMEN
As a member of Bcl-2 protein family, myeloid cell leukemia-1 (Mcl-1) plays a critical role in cell apoptosis and has become a promising anti-cancer drug target. Herein, we designed and synthesized a series of hydantoin derivatives as novel Mcl-1 inhibitors based on our previously developed lead compound. Among them, compound M23 and M24 exhibited good binding affinities against Mcl-1 with Ki values of 0.49 µM and 0.33 µM respectively. Especially, compound M23 exhibited good selectivity over Bcl-xL, whereas compound M24 possessed good selectivity over both Bcl-2 and Bcl-xL. Furthermore, we also investigated the effects of these new Mcl-1 inhibitors on cell proliferation, apoptosis and mitochondrial membrane potential, as well as the stability in plasma.
Asunto(s)
Antineoplásicos , Hidantoínas , Antineoplásicos/química , Apoptosis , Línea Celular Tumoral , Diseño de Fármacos , Hidantoínas/farmacología , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismoRESUMEN
PLX7904 and PLX8394 are novel BRAFV600E inhibitors-BRAFi that are designed to evade the paradoxical MAPK activation, a trait for the name "paradox breakers"-PB. Current FDA approved inhibitors (Vemurafenib, Dabrafenib, Encorafenib) although improved progression-free survival of mtBRAF melanoma patients suffer from this treatment related side effect. mtBRAF Colorectal Cancer (CRC) is resistant to the approved BRAF inhibitors, although combinatorial treatment co-targeting BRAF and EGFR/MEK is offering a promising prospect. In an effort to explore the potential of the novel BRAF inhibitors-PB to impede CRC cell proliferation, they were tested on RKO, HT29 and Colo-205 cells, bearing the BRAFV600E mutation. This study shows that the BRAF paradox breakers PLX7904 and PLX8394 cause a more prolonged MAPK pathway inhibition and achieve a stronger blockage of proliferation and reduced viability than PLX4720, the sister compound of Vemurafenib. In some treatment conditions, cells can undergo apoptosis. Genomic analysis on the more resistant RKO cells treated with PLX7904, PLX8394 and PLX4720 showed similar gene expression pattern, but the alterations imposed by the PB were more intense. Bioinformatic analysis resulted in a short list of genes representing potential master regulators of the cellular response to BRAF inhibitors' treatments. From our results, it is clear that the BRAF paradox breakers present a notable differential regulation of major pathways, like MAPK signalling, apoptosis, cell cycle, or developmental signalling pathways. Combinatorial treatments of BRAFi with Mcl-1 and Notch modulators show a better effect than mono-treatments. Additional pathways could be further exploited in novel efficient combinatorial treatment protocols with BRAFi.
Asunto(s)
Neoplasias Colorrectales/tratamiento farmacológico , Compuestos Heterocíclicos con 2 Anillos/farmacología , Indoles/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Sulfonamidas/farmacología , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Mutación Puntual/efectos de los fármacos , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/metabolismoRESUMEN
Apoptosis is an evolutionarily conserved form of programed cell death (PCD) that has a vital effect on early embryonic development, tissue homeostasis and clearance of damaged cells. Dysregulation of apoptosis can lead to many diseases, such as Alzheimer's disease, cancer, AIDS and heart disease. The anti-apoptotic protein MCL1, a member of the BCL2 family, plays important roles in these physiological and pathological processes. Its high expression is closely related to drug resistances in the treatment of tumor. This review summarizes the structure and function of MCL1, the types of post-translational modifications of MCL1 and their effects on the functions of MCL1, as well as the treatment strategies targeting MCL1 in cancer therapy. The research on the fine regulation of MCL1 will be favorable to the provision of a promising future for the design and screening of MCL1 inhibitors.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/metabolismo , Enfermedad de Alzheimer/metabolismo , Cardiopatías/metabolismo , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Neoplasias/metabolismo , Procesamiento Proteico-Postraduccional , Síndrome de Inmunodeficiencia Adquirida/genética , Síndrome de Inmunodeficiencia Adquirida/terapia , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/terapia , Animales , Apoptosis , Cardiopatías/genética , Cardiopatías/terapia , Humanos , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/genética , Neoplasias/genética , Neoplasias/terapiaRESUMEN
T315I mutation found in chronic myelogenous leukemia (CML) and Ph + ALL patients is the most serious one among resistance against BCR/ABL kinase inhibitors including imatinib and is only responsive to ponatinib (PNT). However, the novel strategy is required to reduce life-threatening adverse effects of PNT including ischemic cardiovascular disease. We examined the mechanism of PNT-induced cytotoxicity against a T315I(+) Ph + ALL cell line, TccY/Sr. PNT induced apoptosis (increased sub G1 cells, and cleaved caspase3 and PARP), and suppressed protein expression of MCL1, cyclin D2 and c-myc, which were reversed by a proteasome inhibitor, MG132, suggesting enhanced proteasomal degradation by PNT. Among BCL2 family inhibitors, MCL1 inhibitors (maritoclax and AZD5991) robustly induced cell death, showing the MCL1-dependent survival of TccY/Sr cells. Decreased MCL1 and c-myc expression by PNT was also observed in T315I(+) MEGA2/STIR cells. PNT suppressed PI3K activation followed by AKT inhibition and GSK3 dephosphorylation. PI3K/AKT inhibitors mimicked PNT, suggesting that PI3K/AKT signaling is important for survival of TccY/Sr cells. Moreover, GSK3 inhibitor (SB216763) reduced PNT-induced cytotoxicity and degradation of c-myc and MCL1. AZD5991 exhibited the synergistic action with PNT, anti-cancer drugs and venetoclax (BCL2 inhibitor), suggesting the utility of MCL1 inhibitor alone or in combination as a future clinical option for Ph + leukemia patients.
Asunto(s)
Antineoplásicos/farmacología , Ciclina D2/metabolismo , Mesilato de Imatinib/farmacología , Imidazoles/farmacología , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Piridazinas/farmacología , Muerte Celular/efectos de los fármacos , Muerte Celular/genética , Línea Celular Tumoral , Ciclina D2/genética , Resistencia a Antineoplásicos/genética , Sinergismo Farmacológico , Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Glucógeno Sintasa Quinasa 3/metabolismo , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leupeptinas/farmacología , Compuestos Macrocíclicos/farmacología , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/antagonistas & inhibidores , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Fosfatidilinositol 3-Quinasas/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacología , Fosforilación , Inhibidores de Proteínas Quinasas/farmacología , Proteína Fosfatasa 2/metabolismo , Proteolisis/efectos de los fármacos , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Pirroles/farmacología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Wortmanina/farmacologíaRESUMEN
The upregulation of the protein myeloid cell leukemia-1 (Mcl-1) is closely associated with various human cancers, which can result in the evasion of apoptosis and a low survival rate. Therefore, developing Mcl-1 inhibitors has become a promising paradigm for cancer therapy. Herein, we designed and synthesized a novel series of tyrosine derivatives, among which compounds 5g, 6l and 6c exhibited very high binding affinity to Mcl-1 with Ki values of 0.18, 0.27 and 0.23 µM, respectively. Interestingly, compound 6l showed not only potent activity against Mcl-1 but also considerable selectivity over Bcl-2 and Bcl-xL, which was rationalized by molecular docking and fragment-centric topographical mapping (FCTM). It is worth noting that compounds 5g, 6l and 6c displayed potent antiproliferative activity against several cancer cell lines and could induce apoptosis of KM3 and HepG2 cells in a dose-dependent manner.
Asunto(s)
Antineoplásicos/farmacología , Diseño de Fármacos , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/antagonistas & inhibidores , Tirosina/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células Hep G2 , Humanos , Modelos Moleculares , Estructura Molecular , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Relación Estructura-Actividad , Tirosina/síntesis química , Tirosina/químicaRESUMEN
Introduction: Myeloid cell leukemia-1 (MCL-1) is an anti-apoptotic member of the B-cell lymphoma-2 (BCL-2) family of proteins that regulates apoptosis. Elevated levels of MCL-1 contribute to tumorigenesis and resistance, not only to conventional chemotherapies but also to targeted therapies, including the BCL-2 selective inhibitor venetoclax. Accordingly, researchers in both the pharmaceutical industry and academia have been actively seeking MCL-1 inhibitors in the quest for new anti-cancer drugs. Areas covered: This review covers the patent literature on the discovery and development of small-molecule inhibitors of MCL-1 since 2017. Expert opinion: Pharmacologic inhibition of MCL-1's oncogenic activity has certainly come of age with the discovery of numerous inhibitors spanning a variety of chemotypes that selectively inhibit MCL-1 in the picomolar range and with on-target cell activity. Furthermore, seminal research by Servier has demonstrated for the first time that MCL-1 inhibition is tolerable in animal models of cancer, paving the way for the six Phase 1 clinical trials that are currently underway for hematological malignancies, among other cancers. After more than a decade of research, the hurdles and obstacles are mostly behind us, and uncovering the therapeutic impact of disrupting the protein-protein interactions of MCL-1 in humans is imminent.
Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/antagonistas & inhibidores , Animales , Descubrimiento de Drogas/métodos , Humanos , Terapia Molecular Dirigida , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Patentes como AsuntoRESUMEN
INTRODUCTION: The myeloid cell leukemia-1 (MCL-1) protein is one of the key anti-apoptotic members of the B-cell lymphoma-2 (BCL-2) protein family. Over-expression of MCL-1 has been closely related to tumor progression as well as to resistance, not only to traditional chemotherapies but also to targeted therapeutics including BCL-2 inhibitors such as ABT-263. Therefore, there has been extensive research and development in the last decade in both academic and industrial settings to address this unmet medical need. Areas covered: This review covers the research and patent literature of the past 10 years in the field of discovery and development of small-molecule inhibitors of the MCL-1 anti-apoptotic protein. Expert opinion: Small-molecule strategies to disrupt the protein-protein interactions between MCL-1 and its pro-apoptotic counterparts, such as BAK and BIM, have recently emerged. Several small-molecules based on different scaffolds describe promising in vitro data as MCL-1 selective inhibitors. While many lead compounds remain at the in vitro preclinical development stage, the two most recent patent applications describe promising in vivo data, and one small molecule inhibitor has recently entered into clinical development. It is such an exciting moment that the long awaited clinical studies will generate some insight into the therapeutic potential of this anti-cancer approach, and possibly facilitate the further development of other early stage inhibitors.
Asunto(s)
Antineoplásicos/farmacología , Diseño de Fármacos , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/antagonistas & inhibidores , Animales , Apoptosis/efectos de los fármacos , Progresión de la Enfermedad , Resistencia a Antineoplásicos , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Patentes como AsuntoRESUMEN
Small-molecule BH3 mimetics are designed to mimic the BH3 domain of BH3-only BCL-2 family members which are antagonists of the prosurvival members (such as BCL-2, BCL-XL and MCL-1). The BH3 mimetics are intended to bind with high affinity to prosurvival proteins, in order to inhibit their functional activity and hence to induce apoptosis in cancer cells. Both navitoclax (BCL-2/BCL-XL antagonist) and ABT-199/venetoclax (BCL-2-selective inhibitor) have demonstrated therapeutic efficacy especially in chronic lymphocytic leukemia (CLL). However, these BH3 mimetics cannot antagonize the prosurvival protein MCL-1 that is overexpressed and involved in therapeutic resistance in CLL. Furthermore, until now, none of the reported small-molecule MCL-1 inhibitors bound to their target with high affinity. The first MCL-1-selective BH3 mimetics capable of high-affinity binding and inducing apoptosis in cancer cells through an on-target mechanism have just been identified. This discovery should advance the translational research to implement novel drugs in treating CLL.