Drug Information

Drug (ID: DG01609) and It's Reported Resistant Information

• Name: A-1155463
• Synonyms: A-1155463; 1235034-55-5; CHEMBL3342332; A1155463; 2-[8-(1,3-Benzothiazol-2-Ylcarbamoyl)-3,4-Dihydroisoquinolin-2(1h)-Yl]-5-(3-{4-[3-(Dimethylamino)prop-1-Yn-1-Yl]-2-Fluorophenoxy}propyl)-1,3-Thiazole-4-Carboxylic Acid; 2-[8-[(2-Benzothiazolylamino)carbonyl]-3,4-dihydro-2(1H)-isoquinolinyl]-5-[3-[4-[3-(dimethylamino)-1-propyn-1-yl]-2-fluorophenoxy]propyl]-4-thiazolecarboxylic acid; A 1155463; SCHEMBL2501550; BCP18309; EX-A1060; BDBM50030754; MFCD29924714; s7800; ZINC163914635; CCG-270355; CS-5398; BS-14688; HY-19725; Q27453707; 2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-(4-(3-(dimethylamino)prop-1-yn-1-yl)-2-fluorophenoxy)propyl)thiazole-4-carboxylic acid; 2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-5-[3-[4-[3-(dimethylamino)prop-1-ynyl]-2-fluorophenoxy]propyl]-1,3-thiazole-4-carboxylic acid; 3CQ
• Drug Resistance Disease(s):
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases)
  Colorectal cancer [ICD-11: 2B91]; [1]
• Formula: 11
• IsoSMILES: CN(C)CC#CC1=CC(=C(C=C1)OCCCC2=C(N=C(S2)N3CCC4=C(C3)C(=CC=C4)C(=O)NC5=NC6=CC=CC=C6S5)C(=O)O)F
• InChI: InChI=1S/C35H32FN5O4S2/c1-40(2)17-6-8-22-14-15-28(26(36)20-22)45-19-7-13-30-31(33(43)44)38-35(47-30)41-18-16-23-9-5-10-24(25(23)21-41)32(42)39-34-37-27-11-3-4-12-29(27)46-34/h3-5,9-12,14-15,20H,7,13,16-19,21H2,1-2H3,(H,43,44)(H,37,39,42)
• InChIKey: SOYCFODXNRVBTI-UHFFFAOYSA-N
• PubChem CID: 59447577

Type(s) of Resistant Mechanism of This Drug

  MRAP: Metabolic Reprogramming via Altered Pathways

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-02: Benign/in-situ/malignant neoplasm

Acute myeloid leukemia [ICD-11: 2A60]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Tyrosine-protein kinase JAK2 (JAK3) [2]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.V617F (c.1849G>T)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SCLC cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: NHL cells; N.A.; Homo sapiens (Human); N.A.
• In Vivo Model: SCID and SCID-bg mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CellTiter-Glo assay; Colony formation assay

Mature B-cell neoplasms/lymphoma [ICD-11: 2A85]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Phosphatase and tensin homolog (PTEN) [3]

• Metabolic Type: Glucose metabolism
• Sensitive Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCL cells; Blood; Homo sapiens (Human); CVCL_UU63
• In Vitro Model: UPF19U cells; Blood; Homo sapiens (Human); N.A.
• In Vitro Model: UPF1H cells; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: PTEN KO was associated with a more distinct phenotype: AKT hyperphosphorylation and overactivation, increased resistance to multiple inhibitors (most of the tested PI3K inhibitors, Bruton tyrosine kinase inhibitor ibrutinib, and BCL2 inhibitor venetoclax), increased glycolytic rates with resistance to 2-deoxy-glucose, and significantly decreased dependence on prosurvival BCR signaling. Our results suggest that the frequent aberrations of the PI3K pathway may rewire associated signaling with lower dependence on BCR signaling, better metabolic and hypoxic adaptation, and targeted therapy resistance in MCL.

Colorectal cancer [ICD-11: 2B91]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Myeloid cell leukemia 1 (Mcl-1) [1]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; H3K27Me3
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: FGFR4 signalling pathway; Regulation; N.A.
• In Vitro Model: Co01 cells; Colon; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: Viability assay
• Mechanism Description: We identify a rescue response that is activated upon BCL-XL inhibition and leads to rapid?FGF2?secretion and subsequent FGFR4-mediated post-translational stabilization of MCL-1. FGFR4 inhibition prevents MCL-1 upregulation and thereby sensitizes CSCs to BCL-XL inhibition. Altogether, our findings suggest a cell transferable induction of a FGF2/FGFR4 rescue response in CRC that is induced upon BCL-XL inhibition and leads to MCL-1 upregulation.

References

• Ref 1: BCL-XL inhibition induces an FGFR4-mediated rescue response in colorectal cancer. Cell Rep. 2022 Feb 15;38(7):110374.
• Ref 2: Exploiting selective BCL-2 family inhibitors to dissect cell survival dependencies and define improved strategies for cancer therapySci Transl Med. 2015 Mar 18;7(279):279ra40. doi: 10.1126/scitranslmed.aaa4642.
• Ref 3: Impact of PIK3CA gain and PTEN loss on mantle cell lymphoma biology and sensitivity to targeted therapies. Blood Adv. 2024 Oct 22;8(20):5279-5289.