Drug Information

Drug (ID: DG01467) and It's Reported Resistant Information

• Name: LY-294002
• Synonyms: 154447-36-6; LY294002; LY 294002; 2-(4-Morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; LY-294002; 2-morpholino-8-phenyl-4H-chromen-4-one; 2-morpholin-4-yl-8-phenyl-4H-chromen-4-one; UNII-31M2U1DVID; 2-morpholin-4-yl-8-phenylchromen-4-one; 2-(morpholin-4-yl)-8-phenylchromen-4-one; 15447-36-6; 2-(morpholin-4-yl)-8-phenyl-4H-chromen-4-one; NSC 697286; 31M2U1DVID; 2-MORPHOLIN-4-YL-7-PHENYL-4H-CHROMEN-4-ONE; CHEMBL98350; 4H-1-Benzopyran-4-one, 2-(4-morpholinyl)-8-phenyl-; CHEBI:65329; SF 1101; LY2; Ly 294002 HCl; LY-294,002; 2-Morpholin-4-yl-8-phenyl-chromen-4-one; BMK1-D5; Lys 294002; 4azt; 2-morpholino-8-phenyl-chromen-4-one; Kinome_3543; Tocris-1130; 1yi3; BiomolKI_000029; Lopac-L-9908; 8-Phenyl-2-(morpholin-4-yl)-chromen-4-one; BiomolKI2_000037; CBiol_002046; Lopac0_000710; SCHEMBL94377; BSPBio_001223; KBioGR_000563; KBioSS_000563; MLS006010131; 2-Morpholino-8-phenylchromone; 2-(4-morpholino)-8-phenyl-4H-1-benzopyran-4-one; 4H-1-Benzopyran-4-one, 2-(4-morpholinyl)-8-phenyl; GTPL6004; ZINC6014; DTXSID6042650; BCBcMAP01_000117; BDBM12915; KBio2_000563; KBio2_003131; KBio2_005699; KBio3_001005; KBio3_001006; EX-A073; SYN1108; BCPP000177; Bio1_000332; Bio1_000821; Bio1_001310; Bio2_000442; Bio2_000922; HMS1362M05; HMS1792M05; HMS1990M05; HMS3229G17; HMS3403M05; HMS3649E04; HMS3654M21; AMY40921; BCP00195; HSCI1_000206; NSC697286; NSC755769; s1105; AKOS017344742; BCP9000880; CCG-100633; CS-0150; DB02656; NSC-697286; NSC-755769; QC-7260; SB10965; SDCCGSBI-0050688.P003; SF-1101; IDI1_002197; NCGC00015622-01; NCGC00015622-02; NCGC00015622-03; NCGC00015622-04; NCGC00015622-05; NCGC00015622-06; NCGC00015622-07; NCGC00015622-23; NCGC00015622-27; NCGC00025020-01; NCGC00025020-02; NCGC00025020-03; NCGC00025020-04; NCGC00179253-01; AC-30295; AS-16252; HY-10108; NCI60_034712; SMR002530642; LY-924002; FT-0660382; M2410; SW217688-2; X7411; EC-000.2341; 2-Morpholino-8-phenyl-4-oxo-4H-1-benzopyran; K00235; J-510126; Q4042503; SR-01000076245-7; 4H-1-Benzopyran-4-one,2-(4-morpholinyl)-8-phenyl-; BRD-K27305650-001-05-9; InSolution LY 294002 - CAS 154447-36-6; LY-294,002 hydrochloride, solid, >=98% (HPLC); LY 294002 - CAS 154447-36-6; 4H-1-Benzopyran-4-one, 2-(4-morpholinyl)-8-phenyl- (9CI); H-1-Benzopyran-4-one, 2-(4-morpholinyl)-8-phenyl- (9CI); LY 294002; 2-(4-Morpholino)-8-phenyl-4H-1-benzopyran-4-one
• Indication:
  In total 1 Indication(s)
  Diarrhea [ICD-11: DA90]; Phase 1; [1]
• Target: Opioid receptor delta (OPRD1); OPRD_HUMAN; [2]
• Formula: 2
• IsoSMILES: C1COCCN1C2=CC(=O)C3=C(O2)C(=CC=C3)C4=CC=CC=C4
• InChI: InChI=1S/C19H17NO3/c21-17-13-18(20-9-11-22-12-10-20)23-19-15(7-4-8-16(17)19)14-5-2-1-3-6-14/h1-8,13H,9-12H2
• InChIKey: CZQHHVNHHHRRDU-UHFFFAOYSA-N
• PubChem CID: 3973
• ChEBI ID: CHEBI:65329
• TTD Drug ID: D0CS2F
• DrugBank ID: DB02656

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

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

Esophageal cancer [ICD-11: 2B70]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: PI3-kinase alpha (PIK3CA) [1]

• Sensitive Disease: Oesophagus adenocarcinoma [ICD-11: 2B70.0]
• Molecule Alteration: Missense mutation; p.E545K (c.1633G>A)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: TE cells; Eye; Oreochromis mossambicus (Mozambique tilapia); CVCL_YD05
• In Vitro Model: KYSE cells; N.A.; N.A.; N.A.
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The missense mutation p.E545K (c.1633G>A) in gene PIK3CA cause the sensitivity of LY-294002 by aberration of the drug's therapeutic target

Melanoma [ICD-11: 2C30]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Serine/threonine-protein kinase mTOR (mTOR) [2]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.H1968Y (c.5902C>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HEK 292T cells; Kidney; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK-8 assay

Prostate cancer [ICD-11: 2C82]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Androgen receptor (AR) [3]

• Sensitive Disease: Prostate cancer [ICD-11: 2C82.0]
• Molecule Alteration: Function; Activation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: LNCaP clone FGC cells; N.A.; Homo sapiens (Human); CVCL_1379
• In Vitro Model: 22Rv-1 cells; Prostate; Homo sapiens (Human); CVCL_1045
• Experiment for Molecule Alteration: Cell protein extraction assay; Western blot assay; qRT-PCR; Luciferase reporter assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: This study revealed the role of p35-CDK5 in between PI3K/Akt and AR by utilizing LNCaP and 22Rv1 cells. Through the TCGA database analysis, we observed a positive correlation between PTEN and p35 expression, implying a potential negative correlation between PI3K/Akt activation and p35-CDK5. Inhibiting PI3K/Akt with LY294002, Capivasertib (AZD5363), or using an inactive Akt mutant significantly increased p35 expression and subsequently enhanced AR stability and activation in PCa cells. On the other hand, CDK5-knockdown reversed these effects. The involvement of the beta-catenin/Egr1-axis was observed in regulating PI3K/Akt inhibition and p35-CDK5 activation, implying a possible mechanistic connection. Importantly, CDK5 knockdown further reduced PI3K/Akt-inhibition-induced AR and cell viability maintenance, suggesting a compensatory role for CDK5-AR in maintaining cell viability under Akt inhibition. In conclusion, PI3K/Akt inhibition could trigger p35-CDK5-dependent AR activation and cell viability, highlighting p35-CDK5 as a critical link connecting PI3K/Akt inhibition to AR activation and pivotal in PCa cell resistance to PI3K/Akt blockade.

References

• Ref 1: PIK3CA mutation status in Japanese esophageal squamous cell carcinomaJ Surg Res. 2008 Apr;145(2):320-6. doi: 10.1016/j.jss.2007.03.044. Epub 2008 Feb 11.
• Ref 2: Analysis of mTOR Gene Aberrations in Melanoma Patients and Evaluation of Their Sensitivity to PI3K-AKT-mTOR Pathway InhibitorsClin Cancer Res. 2016 Feb 15;22(4):1018-27. doi: 10.1158/1078-0432.CCR-15-1110. Epub 2015 Oct 21.
• Ref 3: PI3K/Akt inhibition promotes AR activity and prostate cancer cell proliferation through p35-CDK5 modulation. Biochim Biophys Acta Mol Basis Dis. 2025 Feb;1871(2):167568.