Drug Information

Drug (ID: DG01536) and It's Reported Resistant Information

• Name: Pictilisib
• Synonyms: 957054-30-7; GDC-0941; PICTILISIB; Pictrelisib; GDC0941; GDC 0941; 4-(2-(1H-Indazol-4-yl)-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)thieno[3,2-d]pyrimidin-4-yl)morpholine; 2-(1H-Indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine; UNII-ICY00EMP8P; GDC-0941 (Pictilisib); Pictilisib (GDC-0941); ICY00EMP8P; 4-[2-(1H-indazol-4-yl)-6-[(4-methylsulfonylpiperazin-1-yl)methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine; CHEBI:65326; 957054-30-7 (free base); RG7321; 2-(1H-Indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine; C23H27N7O3S2; 2-(1H-indazol-4-yl)-6-{[4-(methylsulfonyl)piperazin-1-yl]methyl}-4-(morpholin-4-yl)thieno[3,2-d]pyrimidine; 2-(1h-Indazol-4-Yl)-6-{[4-(Methylsulfonyl)piperazin-1-Yl]methyl}-4-Morpholin-4-Yl-Thieno[3,2-D]pyrimidine; 4-(2-(1H-indazol-4-yl)-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)thieno(3,2-d)pyrimidin-4-yl)morpholine; GD9; Pictilisib [USAN:INN]; Pictilisib (USAN); Kinome_3719; GDC0941(Pictilisib); 957054-50-1; Pictilisib; GDC-0941; 2-(1H-Indazol-4-yl)-6-[[4-(methylsulfonyl)-1-piperazinyl]methyl]-4-(4-morpholinyl)thieno[3,2-d]pyrimidine; MLS006010057; SCHEMBL190812; CHEMBL521851; GTPL5682; BDBM25028; DTXSID40241930; EX-A167; SYN1041; HMS2043A16; HMS3244H06; HMS3244H10; HMS3244H14; HMS3265I05; HMS3265I06; HMS3265J05; HMS3265J06; HMS3654K13; HMS3744A19; AOB87310; BCP01714; CDC-0941; EX-A1536; GNE 0941; MFCD11616196; NSC755385; NSC800852; s1065; ZINC16052714; AKOS015966503; BCP9000715; CCG-264801; CS-0081; DB11663; NSC-755385; NSC-800852; QC-4780; RG-7321; SB19941; NCGC00187482-01; NCGC00187482-03; NCGC00187482-10; 2-(1H-indazol-4-yl)-6-((4-(methanesulfonyl)piperazin-1-yl)methyl)-4-(morpholin-4-yl)thieno(3,2-d)pyrimidine; AC-32623; AS-19377; HY-50094; SMR004701219; Thieno(3,2-d)pyrimidine, 2-(1H-indazol-4-yl)-6-((4-(methylsulfonyl)-1-piperazinyl]methyl)-4-(4-morpholinyl)-; FT-0696889; SW202556-4; X7409; EC-000.2335; D10189; 054G307; A845396; J-513238; BRD-K52911425-001-02-3; Q27088388; C532162000; 2-(1H-indazol-4-yl)-6-{[4-(methylsulfonyl)piperazin-1-yl]methyl}-4-morpholin-4-ylthieno[3,2-d]pyrimidine; 4-[2-(1H-indazol-4-yl)-6-[(4-methanesulfonylpiperazin-1-yl)methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine; 4-[2-(1H-indazol-4-yl)-6-[(4-methylsulfonyl-1-piperazinyl)methyl]-4-thieno[3,2-d]pyrimidinyl]morpholine; Thieno[3,2-d]pyrimidine,2-(1H-indazol-4-yl)-6-[[4-(methylsulfonyl)-1-piperazinyl]methyl]-4-(4-morpholinyl)-
• Indication:
  In total 1 Indication(s)
  Myelofibrosis [ICD-11: 2A20]; Phase 2; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (1 diseases)
  Bladder cancer [ICD-11: 2C94]; [1]
• Target: Janus kinase 2 (JAK-2); JAK2_HUMAN; [2]
• Formula: 5
• IsoSMILES: CS(=O)(=O)N1CCN(CC1)CC2=CC3=C(S2)C(=NC(=N3)C4=C5C=NNC5=CC=C4)N6CCOCC6
• InChI: InChI=1S/C23H27N7O3S2/c1-35(31,32)30-7-5-28(6-8-30)15-16-13-20-21(34-16)23(29-9-11-33-12-10-29)26-22(25-20)17-3-2-4-19-18(17)14-24-27-19/h2-4,13-14H,5-12,15H2,1H3,(H,24,27)
• InChIKey: LHNIIDJUOCFXAP-UHFFFAOYSA-N
• PubChem CID: 17755052
• ChEBI ID: CHEBI:65326
• TTD Drug ID: D0G8BM
• DrugBank ID: DB11663

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

Melanoma [ICD-11: 2C30]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [2]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: ICH assay
• Experiment for Drug Resistance: Plasma level assay; Electrochemiluminescense assay

Breast cancer [ICD-11: 2C60]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: PI3-kinase alpha (PIK3CA) [3]

• Sensitive Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Molecule Alteration: Missense mutation; p.E545K (c.1633G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vivo Model: Female NCR nu/nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: PCR DNA sequencing assay
• Experiment for Drug Resistance: CellTiter-Glo assay; IC50 assay

Bladder cancer [ICD-11: 2C94]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

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

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Missense mutation; p.D549Y (c.1645G>T)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MEK/ERK signaling pathway; Activation; hsa04011
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: J82 cells; Bladder; Homo sapiens (Human); CVCL_0359
• In Vitro Model: RT4 cells; Bladder; Homo sapiens (Human); CVCL_0036
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: TCCSuP cells; Bladder; Homo sapiens (Human); CVCL_1738
• In Vivo Model: NSG mouse PDX model; Mus musculus
• Experiment for Drug Resistance: MTS assay; FACS assay
• Mechanism Description: Pictilisib activated the compensatory MEK/ERK pathways that likely contributed to pictilisib resistance, which was reversed by co-treatment with the RAF inhibitor sorafenib. RNA-sequencing of tumors resistant to treatment suggested that LSP1 down-regulation correlated with drug resistance.

Key Molecule: Phosphatase and tensin homolog (PTEN) [1]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Missense mutation; p.N48I (c.143A>T)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MEK/ERK signaling pathway; Activation; hsa04011
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: J82 cells; Bladder; Homo sapiens (Human); CVCL_0359
• In Vitro Model: RT4 cells; Bladder; Homo sapiens (Human); CVCL_0036
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: TCCSuP cells; Bladder; Homo sapiens (Human); CVCL_1738
• In Vivo Model: NSG mouse PDX model; Mus musculus
• Experiment for Drug Resistance: MTS assay; FACS assay
• Mechanism Description: Pictilisib activated the compensatory MEK/ERK pathways that likely contributed to pictilisib resistance, which was reversed by co-treatment with the RAF inhibitor sorafenib. RNA-sequencing of tumors resistant to treatment suggested that LSP1 down-regulation correlated with drug resistance.

References

• Ref 1: The Phosphatidylinositol 3-Kinase Pathway as a Potential Therapeutic Target in Bladder CancerClin Cancer Res. 2017 Nov 1;23(21):6580-6591. doi: 10.1158/1078-0432.CCR-17-0033. Epub 2017 Aug 14.
• Ref 2: First-in-human phase I study of pictilisib (GDC-0941), a potent pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor, in patients with advanced solid tumorsClin Cancer Res. 2015 Jan 1;21(1):77-86. doi: 10.1158/1078-0432.CCR-14-0947. Epub 2014 Nov 4.
• Ref 3: PIK3CA and AKT1 mutations have distinct effects on sensitivity to targeted pathway inhibitors in an isogenic luminal breast cancer model systemClin Cancer Res. 2013 Oct 1;19(19):5413-22. doi: 10.1158/1078-0432.CCR-13-0884. Epub 2013 Jul 25.