Myeloid cell leukemia 1 (MCL-1): Structural characteristics and application in cancer therapy

Mittal, Pooja; Singh, Sujata; Sinha, Rajesh; Shrivastava, Anju; Singh, Archana; Singh, Ishwar

doi:10.1016/j.ijbiomac.2021.07.166

Cited by 26 publications

(16 citation statements)

References 168 publications

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“…It contains a globular portion at the C-terminus that is homologous to the other Bcl-2 family members ( Fig 2 ) [ 30 , 31 ] and an N-terminal extension not found in the other Bcl-2 family members [ 32 ]. This extension consists of approximately 160 residues that contain multiple regulatory regions that modulate MCL1 stability [ 32 ] as well as a tag that targets MCL1 to the mitochondrial matrix [ 33 ]. The globular region of MCL1 contains the four BH motifs that fold to make the BH3 binding groove.…”

Section: Introductionmentioning

confidence: 99%

Phylogenetic analysis of the MCL1 BH3 binding groove and rBH3 sequence motifs in the p53 and INK4 protein families

McGriff

Placzek

2023

PLoS ONE

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B-cell lymphoma 2 (Bcl-2) proteins are central, conserved regulators of apoptosis. Bcl-2 family function is regulated by binding interactions between the Bcl-2 homology 3 (BH3) motif in pro-apoptotic family members and the BH3 binding groove found in both the pro-apoptotic effector and anti-apoptotic Bcl-2 family members. A novel motif, the reverse BH3 (rBH3), has been shown to interact with the anti-apoptotic Bcl-2 homolog MCL1 (Myeloid cell leukemia 1) and have been identified in the p53 homolog p73, and the CDK4/6 (cyclin dependent kinase 4/6) inhibitor p18INK4c, (p18, cyclin-dependent kinase 4 inhibitor c). To determine the conservation of rBH3 motif, we first assessed conservation of MCL1’s BH3 binding groove, where the motif binds. We then constructed neighbor-joining phylogenetic trees of the INK4 and p53 protein families and analyzed sequence conservation using sequence logos of the rBH3 locus. This showed the rBH3 motif is conserved throughout jawed vertebrates p63 and p73 sequences and in chondrichthyans, amphibians, mammals, and some reptiles in p18. Finally, a potential rBH3 motif was identified in mammalian and osteichthyan p19INK4d (p19, cyclin dependent kinase 4 inhibitor d). These findings demonstrate that the interaction between MCL1 and other cellular proteins mediated by the rBH3 motif may be conserved throughout jawed vertebrates.

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Section: Introductionmentioning

confidence: 99%

Phylogenetic analysis of the MCL1 BH3 binding groove and rBH3 sequence motifs in the p53 and INK4 protein families

McGriff

Placzek

2023

PLoS ONE

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“…Our studies with obatoclax (GX15-070), one of the pan-Bcl-2 inhibitors capable of inhibiting Mcl-1, demonstrated a potent single-agent activity against oral cancer cells in vitro and in vivo by inducing a rather non-canonical form of cell death, namely “necroptosis” [ 57 ]. Further, a number of excellent articles have reviewed the recent development and current status in the clinical trials of many of these compounds [ 104 , 108 , 109 , 114 – 116 ].…”

Section: Therapeutic Targeting Of Mcl-1mentioning

confidence: 99%

Myeloid cell leukemia-1: a formidable barrier to anticancer therapeutics and the quest of targeting it

Sulkshane

Teni

2022

Exploration of Targeted Anti-Tumor Therapy

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The antiapoptotic B cell lymphoma-2 (Bcl-2) family members are apical regulators of the intrinsic pathway of apoptosis that orchestrate mitochondrial outer membrane permeabilization (MOMP) through interactions with their proapoptotic counterparts. Overexpression of antiapoptotic Bcl-2 family proteins has been linked to therapy resistance and poor prognosis in diverse cancers. Among the antiapoptotic Bcl-2 family members, predominant overexpression of the prosurvival myeloid cell leukemia-1 (Mcl-1) has been reported in a myriad of hematological malignancies and solid tumors, contributing to therapy resistance and poor outcomes, thus making it a potential druggable target. The unique structure of Mcl-1 and its complex regulatory mechanism makes it an adaptive prosurvival switch that ensures tumor cell survival despite therapeutic intervention. This review focusses on diverse mechanisms adopted by tumor cells to maintain sustained elevated levels of Mcl-1 and how high Mcl-1 levels contribute to resistance in conventional as well as targeted therapies. Moreover, recent developments in the Mcl-1-targeted therapeutics and the underlying challenges and considerations in designing novel Mcl-1 inhibitors are also discussed.

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Section: Scheme 4 Synthesis Of Quinazolinones Via An Acceptorless Coupling Of O-aminobenzamidesmentioning

confidence: 99%

“…In this work, the role of the copper catalyst, as well as the mechanistic insides, were carefully analyzed through a combined experimental and computational investigation. Some of the synthesized cyclic amino acids, tetrahydroquinoline-3-carboxylic acids, are important building blocks in medicinal chemistry, such as myeloid cell leukemia-1 (Mcl-1) inhibitor (Figure 4) [44]. The optimal conditions of the copper catalyst were carefully studied, and the best results were obtained in the presence of 5 mol% of CuOTf * 0.5 C6H6 as the copper source, along with the use of 10 mol% of a hybrid ligand of pyridine and benzoxazole in HFIP solvent at room temperature for 12 h. From these conditions, the scope and limitations were evaluated for the selective amination of aromatic C(sp2)−H bonds, even in the presence of potentially detrimental functionalities, including double and triple bonds (Scheme 12).…”

Section: Scheme 4 Synthesis Of Quinazolinones Via An Acceptorless Coupling Of O-aminobenzamidesmentioning

confidence: 99%

Advances in Green Catalysis for the Synthesis of Medicinally Relevant N-Heterocycles

et al. 2021

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N-heterocycles, both saturated and unsaturated, are ubiquitous biologically active molecules that are extremely appealing scaffolds in drug discovery programs. Although classical synthetic methods have been developed to access many relevant N-heterocyclic scaffolds, representing well-established and reliable routes, some do not meet the needs of sustainability. In this context, several advances have been made towards the sustainable synthesis of N-heterocycles. This review focuses on the most recent examples from the last five years of catalytic synthesis of several heterocyclic compounds of medicinal relevance. Thus, the synthesis of isoindoloquinazolines, quinazolines and azaindoles, among others, are covered. The synthetic methods selected include the use of homogeneous and heterogeneous catalysts and the use of alternative and sustainable methods such as, for example, metal-catalyzed acceptorless coupling and one-pot reactions. The green aspects of the individual synthetic approaches are highlighted, and the scope of each methodology is described.

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Myeloid cell leukemia 1 (MCL-1): Structural characteristics and application in cancer therapy

Cited by 26 publications

References 168 publications

Phylogenetic analysis of the MCL1 BH3 binding groove and rBH3 sequence motifs in the p53 and INK4 protein families

Phylogenetic analysis of the MCL1 BH3 binding groove and rBH3 sequence motifs in the p53 and INK4 protein families

Myeloid cell leukemia-1: a formidable barrier to anticancer therapeutics and the quest of targeting it

Advances in Green Catalysis for the Synthesis of Medicinally Relevant N-Heterocycles

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