Details of the Drug Combination

General Information of Drug Combination (ID: DCJAOK9)

• Drug Combination Name: GDC0941 + Podofilox
• Indication: Glioblastoma; Status: Investigative [1]
• Component Drugs:
  GDC0941 (DM1YAK6): Small molecular drug
  Podofilox (DMT2EJP): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: JHH-136
  Zero Interaction Potency (ZIP) Score: 28.363
  Bliss Independence Score: 29.642
  Loewe Additivity Score: 3.694
  LHighest Single Agent (HSA) Score: 4.37

Molecular Interaction Atlas of This Drug Combination

Indication(s) of GDC0941

Disease Entry	ICD 11	Status	REF
Breast cancer	2C60-2C65	Phase 2	[2]
Non-hodgkin lymphoma	2B33.5	Phase 2	[3]
Solid tumour/cancer	2A00-2F9Z	Phase 2	[3]

GDC0941 Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
PI3-kinase gamma (PIK3CG)	TTHBTOP	PK3CG_HUMAN	Inhibitor	[6]

GDC0941 Interacts with 54 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[7]
Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform (PIK3CD)	OTOMP6TH	PK3CD_HUMAN	Decreases Activity	[8]
Bcl-2-like protein 11 (BCL2L11)	OTNQQWFJ	B2L11_HUMAN	Increases Expression	[9]
Forkhead box protein O3 (FOXO3)	OTHXQG4P	FOXO3_HUMAN	Decreases Phosphorylation	[10]
L-lactate dehydrogenase A chain (LDHA)	OTN7K4XB	LDHA_HUMAN	Decreases Expression	[11]
Myc proto-oncogene protein (MYC)	OTPV5LUK	MYC_HUMAN	Decreases Expression	[10]
High affinity nerve growth factor receptor (NTRK1)	OTJORQAU	NTRK1_HUMAN	Decreases Activity	[8]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Increases Expression	[12]
Cyclin-dependent kinase 1 (CDK1)	OTW1SC2N	CDK1_HUMAN	Decreases Phosphorylation	[13]
Cathepsin B (CTSB)	OTP9G5QB	CATB_HUMAN	Increases Expression	[14]
Hepatocyte growth factor receptor (MET)	OT7K55MU	MET_HUMAN	Increases Expression	[5]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[15]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[12]
Solute carrier family 2, facilitated glucose transporter member 1 (SLC2A1)	OTA675TJ	GTR1_HUMAN	Decreases Expression	[11]
Lysosome-associated membrane glycoprotein 1 (LAMP1)	OTYE92QY	LAMP1_HUMAN	Increases Expression	[14]
G2/mitotic-specific cyclin-B1 (CCNB1)	OT19S7E5	CCNB1_HUMAN	Decreases Expression	[13]
Transcription factor EB (TFEB)	OTJUJJQY	TFEB_HUMAN	Increases Expression	[14]
Receptor tyrosine-protein kinase erbB-3 (ERBB3)	OTRSST0A	ERBB3_HUMAN	Increases Expression	[5]
Ribosomal protein S6 kinase beta-1 (RPS6KB1)	OTAELNGX	KS6B1_HUMAN	Decreases Phosphorylation	[16]
Eukaryotic translation initiation factor 4B (EIF4B)	OTE8TXA8	IF4B_HUMAN	Decreases Phosphorylation	[12]
G1/S-specific cyclin-D1 (CCND1)	OT8HPTKJ	CCND1_HUMAN	Decreases Expression	[13]
G1/S-specific cyclin-E1 (CCNE1)	OTLD7UID	CCNE1_HUMAN	Decreases Expression	[12]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Increases Activity	[17]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Increases Activity	[17]
RAC-alpha serine/threonine-protein kinase (AKT1)	OT8H2YY7	AKT1_HUMAN	Decreases Phosphorylation	[8]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[12]
Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform (PIK3CB)	OTO8JQJA	PK3CB_HUMAN	Affects Activity	[8]
Serine/threonine-protein kinase mTOR (MTOR)	OTHH8KU7	MTOR_HUMAN	Decreases Activity	[18]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[19]
Cyclin-dependent kinase inhibitor 1B (CDKN1B)	OTNY5LLZ	CDN1B_HUMAN	Increases Expression	[12]
Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform (PIK3CG)	OT3FAU4Y	PK3CG_HUMAN	Affects Activity	[8]
Glycogen synthase kinase-3 beta (GSK3B)	OTL3L14B	GSK3B_HUMAN	Decreases Phosphorylation	[16]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Cleavage	[10]
Small ribosomal subunit protein eS6 (RPS6)	OTT4D1LN	RS6_HUMAN	Decreases Phosphorylation	[15]
Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1)	OT2YYI1A	MCL1_HUMAN	Decreases Expression	[5]
Eukaryotic translation initiation factor 4E-binding protein 1 (EIF4EBP1)	OTHBQVD5	4EBP1_HUMAN	Decreases Phosphorylation	[20]
Cyclin-G2 (CCNG2)	OTII38K2	CCNG2_HUMAN	Increases Expression	[5]
Hypoxia-inducible factor 1-alpha (HIF1A)	OTADSC03	HIF1A_HUMAN	Decreases Expression	[11]
Carbonic anhydrase 9 (CA9)	OTNA51XT	CAH9_HUMAN	Decreases Expression	[11]
Atos homolog protein A (ATOSA)	OTWFM5G0	ATOSA_HUMAN	Increases Expression	[5]
Bcl2-associated agonist of cell death (BAD)	OT63ERYM	BAD_HUMAN	Decreases Phosphorylation	[20]
Proline-rich AKT1 substrate 1 (AKT1S1)	OT4JHN4Y	AKTS1_HUMAN	Decreases Phosphorylation	[21]
Serine/threonine-protein kinase Sgk3 (SGK3)	OTQ6QO99	SGK3_HUMAN	Decreases Phosphorylation	[13]
Phosphoinositide-3-kinase-interacting protein 1 (PIK3IP1)	OTWE5G4T	P3IP1_HUMAN	Increases Expression	[5]
UDP-N-acetylglucosamine--peptide N-acetylglucosaminyltransferase 110 kDa subunit (OGT)	OT1Z1ZXE	OGT1_HUMAN	Increases Response To Substance	[22]
RNA cytidine acetyltransferase (NAT10)	OT6JQO26	NAT10_HUMAN	Affects Response To Substance	[23]
GTPase KRas (KRAS)	OT78QCN8	RASK_HUMAN	Increases Response To Substance	[5]
Epidermal growth factor receptor (EGFR)	OTAPLO1S	EGFR_HUMAN	Increases Response To Substance	[5]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Affects Transport	[24]
Dendrin (DDN)	OTM52ZF5	DEND_HUMAN	Increases Response To Substance	[22]
Receptor tyrosine-protein kinase erbB-2 (ERBB2)	OTOAUNCK	ERBB2_HUMAN	Increases Response To Substance	[25]
Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN (PTEN)	OTOWDUNT	PTEN_HUMAN	Increases Response To Substance	[21]
Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (PIK3CA)	OTTOMI8J	PK3CA_HUMAN	Increases Response To Substance	[25]
Pro-neuregulin-1, membrane-bound isoform (NRG1)	OTZO6F1X	NRG1_HUMAN	Decreases Response To Substance	[26]

Indication(s) of Podofilox

Disease Entry	ICD 11	Status	REF
Condyloma	1A95	Approved	[4]
External genital and perianal wart	1A95	Approved	[4]
Verruca vulgaris	1E80	Approved	[4]

Podofilox Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
DNA topoisomerase II (TOP2)	TT0IHXV	TOP2A_HUMAN; TOP2B_HUMAN	Modulator	[27]

Podofilox Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[28]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[28]

Podofilox Interacts with 5 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[29]
Microtubule-associated protein tau (MAPT)	OTMTP2Z7	TAU_HUMAN	Decreases Expression	[30]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[29]
Caspase-2 (CASP2)	OTUDYSPP	CASP2_HUMAN	Increases Activity	[29]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Activity	[29]

References

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• [2] Phase II Randomized Preoperative Window-of-Opportunity Study of the PI3K Inhibitor Pictilisib Plus Anastrozole Compared With Anastrozole Alone in P... J Clin Oncol. 2016 Jun 10;34(17):1987-94.
• [3] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 5682).
• [4] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [5] Phosphoinositide 3-kinase (PI3K) pathway alterations are associated with histologic subtypes and are predictive of sensitivity to PI3K inhibitors in lung cancer preclinical models. Clin Cancer Res. 2012 Dec 15;18(24):6771-83. doi: 10.1158/1078-0432.CCR-12-2347. Epub 2012 Nov 7.
• [6] Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov. 2009 Aug;8(8):627-44.
• [7] A multifactorial approach to hepatobiliary transporter assessment enables improved therapeutic compound development. Toxicol Sci. 2013 Nov;136(1):216-41.
• [8] The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer. J Med Chem. 2008 Sep 25;51(18):5522-32. doi: 10.1021/jm800295d.
• [9] Intermittent administration of MEK inhibitor GDC-0973 plus PI3K inhibitor GDC-0941 triggers robust apoptosis and tumor growth inhibition. Cancer Res. 2012 Jan 1;72(1):210-9. doi: 10.1158/0008-5472.CAN-11-1515. Epub 2011 Nov 14.
• [10] The PI3K inhibitor GDC-0941 combines with existing clinical regimens for superior activity in multiple myeloma. Oncogene. 2014 Jan 16;33(3):316-25. doi: 10.1038/onc.2012.594. Epub 2013 Jan 14.
• [11] GDC-0941 inhibits metastatic characteristics of thyroid carcinomas by targeting both the phosphoinositide-3 kinase (PI3K) and hypoxia-inducible factor-1 (HIF-1) pathways. J Clin Endocrinol Metab. 2011 Dec;96(12):E1934-43. doi: 10.1210/jc.2011-1426. Epub 2011 Oct 12.
• [12] The novel dual PI3K/mTOR inhibitor GDC-0941 synergizes with the MEK inhibitor U0126 in non-small cell lung cancer cells. Mol Med Rep. 2012 Feb;5(2):503-8. doi: 10.3892/mmr.2011.682. Epub 2011 Nov 16.
• [13] Nuclear phospho-Akt increase predicts synergy of PI3K inhibition and doxorubicin in breast and ovarian cancer. Sci Transl Med. 2010 Sep 8;2(48):48ra66. doi: 10.1126/scitranslmed.3000630.
• [14] GDC-0941 enhances the lysosomal compartment via TFEB and primes glioblastoma cells to lysosomal membrane permeabilization and cell death. Cancer Lett. 2013 Feb 1;329(1):27-36. doi: 10.1016/j.canlet.2012.09.007. Epub 2012 Sep 18.
• [15] Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941. Cancer Cell. 2009 May 5;15(5):429-40. doi: 10.1016/j.ccr.2009.03.020.
• [16] Biological properties of potent inhibitors of class I phosphatidylinositide 3-kinases: from PI-103 through PI-540, PI-620 to the oral agent GDC-0941. Mol Cancer Ther. 2009 Jul;8(7):1725-38. doi: 10.1158/1535-7163.MCT-08-1200. Epub 2009 Jul 7.
• [17] Simultaneous inhibition of pan-phosphatidylinositol-3-kinases and MEK as a potential therapeutic strategy in peripheral T-cell lymphomas. Haematologica. 2013 Jan;98(1):57-64. doi: 10.3324/haematol.2012.068510. Epub 2012 Jul 16.
• [18] Mechanisms of apoptosis induction by simultaneous inhibition of PI3K and FLT3-ITD in AML cells in the hypoxic bone marrow microenvironment. Cancer Lett. 2013 Feb 1;329(1):45-58. doi: 10.1016/j.canlet.2012.09.020. Epub 2012 Oct 2.
• [19] PI3K inhibition enhances doxorubicin-induced apoptosis in sarcoma cells. PLoS One. 2012;7(12):e52898. doi: 10.1371/journal.pone.0052898. Epub 2012 Dec 31.
• [20] Pim 1 kinase inhibitor ETP-45299 suppresses cellular proliferation and synergizes with PI3K inhibition. Cancer Lett. 2011 Jan 28;300(2):145-53. doi: 10.1016/j.canlet.2010.09.016. Epub 2010 Nov 3.
• [21] Isoform-specific phosphoinositide 3-kinase inhibitors exert distinct effects in solid tumors. Cancer Res. 2010 Feb 1;70(3):1164-72. doi: 10.1158/0008-5472.CAN-09-2525. Epub 2010 Jan 26.
• [22] Modulators of sensitivity and resistance to inhibition of PI3K identified in a pharmacogenomic screen of the NCI-60 human tumor cell line collection. PLoS One. 2012;7(9):e46518. doi: 10.1371/journal.pone.0046518. Epub 2012 Sep 28.
• [23] Regulatory roles of NAT10 in airway epithelial cell function and metabolism in pathological conditions. Cell Biol Toxicol. 2023 Aug;39(4):1237-1256. doi: 10.1007/s10565-022-09743-z. Epub 2022 Jul 25.
• [24] Role of P-glycoprotein and breast cancer resistance protein-1 in the brain penetration and brain pharmacodynamic activity of the novel phosphatidylinositol 3-kinase inhibitor GDC-0941. Drug Metab Dispos. 2010 Sep;38(9):1422-6. doi: 10.1124/dmd.110.034256. Epub 2010 Jun 3.
• [25] Predictive biomarkers of sensitivity to the phosphatidylinositol 3' kinase inhibitor GDC-0941 in breast cancer preclinical models. Clin Cancer Res. 2010 Jul 15;16(14):3670-83. doi: 10.1158/1078-0432.CCR-09-2828. Epub 2010 May 7.
• [26] Suppression of HER2/HER3-mediated growth of breast cancer cells with combinations of GDC-0941 PI3K inhibitor, trastuzumab, and pertuzumab. Clin Cancer Res. 2009 Jun 15;15(12):4147-56. doi: 10.1158/1078-0432.CCR-08-2814. Epub 2009 Jun 9.
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• [29] Polyalkoxybenzenes from plants. 5. Parsley seed extract in synthesis of azapodophyllotoxins featuring strong tubulin destabilizing activity in the sea urchin embryo and cell culture assays. J Med Chem. 2011 Oct 27;54(20):7138-49. doi: 10.1021/jm200737s. Epub 2011 Sep 29.
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