Molecule Information

General Information of the Molecule (ID: Mol04330)

• Name: Apoptosis regulator Bcl-2 (BCL2) ,Homo sapiens
• Molecule Type: Protein
• Gene Name: BCL2
• Gene ID: 596
• Sequence:
  MAHAGRTGYDNREIVMKYIHYKLSQRGYEWDAGDVGAAPPGAAPAPGIFSSQPGHTPHPA
  ASRDPVARTSPLQTPAAPGAAAGPALSPVPPVVHLTLRQAGDDFSRRYRRDFAEMSSQL
  H LTPFTARGRFATVVEELFRDGVNWGRIVAFFEFGGVMCVESVNREMSPLVDNIALWMT
  EY LNRHLHTWIQDNGGWDAFVELYGPSMRPLFDFSWLSLKTLLSLALVGACITLGAYLG
  HK
• Function: Suppresses apoptosis in a variety of cell systems includingfactor-dependent lymphohematopoietic and neural cells . Regulates cell death by controlling the mitochondrialmembrane permeability . Appears to function in afeedback loop system with caspases . Inhibits caspaseactivity either by preventing the release of cytochrome c from themitochondria and/or by binding to the apoptosis-activating factor . Also acts as an inhibitor of autophagy:interacts with BECN1 and AMBRA1 during non-starvation conditions andinhibits their autophagy function . May attenuate inflammation by impairing NLRP1-inflammasome activation, hence CASP1 activation and IL1B release. {ECO:0000269|PubMed:1508712,ECO:0000269|PubMed:17418785, ECO:0000269|PubMed:18570871,ECO:0000269|PubMed:20889974, ECO:0000269|PubMed:21358617,ECO:0000269|PubMed:8183370, ECO:0000303|PubMed:11368354}.
• Uniprot ID: BCL2_HUMAN
• Ensembl ID: ENSG0000017179114
• HGNC ID: HGNC:990

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Investigative Drug(s) 2 drug(s) in total

IMC-HA

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Acute myeloid leukemia [ICD-11: 2A60.0] [1]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Sensitive Drug: IMC-HA
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: MEK/ERK signaling pathway; Inhibition; hsa04011
• In Vitro Model: THP-1 cells; monocytic; Homo sapiens (Human); N.A.
• In Vitro Model: U937 cells; Blood; Homo sapiens (Human); CVCL_0007
• Experiment for Molecule Alteration: Western blot assay; Molecular docking assay
• Experiment for Drug Resistance: Cell viability assay; Apoptosis assay; Cell cycle assay; HDAC activity assay
• Mechanism Description: In this study, we designed and synthesized dual cyclooxygenase-2 (COX-2) and histone deacetylase (HDAC) inhibitors, IMC-HA and IMC-OPD, and applied them for the treatment of AML. IMC-HA comprised a COX-2 inhibitor skeleton of indomethacin (IMC) and an HDAC inhibitor moiety of the hydroxamic group and was found to exhibit potent antiproliferative activity against AML cells (THP-1 and U937) and low cytotoxicity toward normal cells. Molecular docking simulations suggested that IMC-HA had a high binding affinity for HDAC and COX-2, with binding energies of -6.8 and -9.0 kcal/mol, respectively. Mechanistic studies revealed that IMC-HA induced apoptosis and G0/G1 phase arrest in AML cells, which were characterized by alterations in the expression of apoptotic and cell cycle-related proteins. Further study demonstrated that IMC-HA also inhibited the MEK/ERK signaling pathway in AML cells. Overall, we believe that IMC-HA could serve as a potent COX-2/HDAC dual inhibitor and improve the treatment of AML.

IMC-OPD

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Acute myeloid leukemia [ICD-11: 2A60.0] [1]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Sensitive Drug: IMC-OPD
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: MEK/ERK signaling pathway; Inhibition; hsa04011
• In Vitro Model: THP-1 cells; monocytic; Homo sapiens (Human); N.A.
• In Vitro Model: U937 cells; Blood; Homo sapiens (Human); CVCL_0007
• Experiment for Molecule Alteration: Western blot assay; Molecular docking assay
• Experiment for Drug Resistance: Cell viability assay; Apoptosis assay; Cell cycle assay; HDAC activity assay
• Mechanism Description: In this study, we designed and synthesized dual cyclooxygenase-2 (COX-2) and histone deacetylase (HDAC) inhibitors, IMC-HA and IMC-OPD, and applied them for the treatment of AML. IMC-HA comprised a COX-2 inhibitor skeleton of indomethacin (IMC) and an HDAC inhibitor moiety of the hydroxamic group and was found to exhibit potent antiproliferative activity against AML cells (THP-1 and U937) and low cytotoxicity toward normal cells. Molecular docking simulations suggested that IMC-HA had a high binding affinity for HDAC and COX-2, with binding energies of -6.8 and -9.0 kcal/mol, respectively. Mechanistic studies revealed that IMC-HA induced apoptosis and G0/G1 phase arrest in AML cells, which were characterized by alterations in the expression of apoptotic and cell cycle-related proteins. Further study demonstrated that IMC-HA also inhibited the MEK/ERK signaling pathway in AML cells. Overall, we believe that IMC-HA could serve as a potent COX-2/HDAC dual inhibitor and improve the treatment of AML.

References

• Ref 1: A potent dual inhibitor targeting COX-2 and HDAC of acute myeloid leukemia cells. Mol Divers. 2025 Jun;29(3):2433-2444.