Details of the Drug Combination

General Information of Drug Combination (ID: DC1SD8X)

Drug Combination Name
GDC0941 Cotellic
Indication
Disease Entry Status REF
Solid Tumors Phase 1 [1]
Component Drugs GDC0941   DM1YAK6 Cotellic   DMF9M57
Small molecular drug Small molecular drug
2D MOL 2D MOL
3D MOL 3D MOL

Molecular Interaction Atlas of This Drug Combination

Molecular Interaction Atlas (MIA)
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 [8]
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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 [9]
Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform (PIK3CD) OTOMP6TH PK3CD_HUMAN Decreases Activity [10]
Bcl-2-like protein 11 (BCL2L11) OTNQQWFJ B2L11_HUMAN Increases Expression [11]
Forkhead box protein O3 (FOXO3) OTHXQG4P FOXO3_HUMAN Decreases Phosphorylation [12]
L-lactate dehydrogenase A chain (LDHA) OTN7K4XB LDHA_HUMAN Decreases Expression [13]
Myc proto-oncogene protein (MYC) OTPV5LUK MYC_HUMAN Decreases Expression [12]
High affinity nerve growth factor receptor (NTRK1) OTJORQAU NTRK1_HUMAN Decreases Activity [10]
Cellular tumor antigen p53 (TP53) OTIE1VH3 P53_HUMAN Increases Expression [14]
Cyclin-dependent kinase 1 (CDK1) OTW1SC2N CDK1_HUMAN Decreases Phosphorylation [15]
Cathepsin B (CTSB) OTP9G5QB CATB_HUMAN Increases Expression [16]
Hepatocyte growth factor receptor (MET) OT7K55MU MET_HUMAN Increases Expression [7]
Poly polymerase 1 (PARP1) OT310QSG PARP1_HUMAN Increases Cleavage [17]
Apoptosis regulator Bcl-2 (BCL2) OT9DVHC0 BCL2_HUMAN Decreases Expression [14]
Solute carrier family 2, facilitated glucose transporter member 1 (SLC2A1) OTA675TJ GTR1_HUMAN Decreases Expression [13]
Lysosome-associated membrane glycoprotein 1 (LAMP1) OTYE92QY LAMP1_HUMAN Increases Expression [16]
G2/mitotic-specific cyclin-B1 (CCNB1) OT19S7E5 CCNB1_HUMAN Decreases Expression [15]
Transcription factor EB (TFEB) OTJUJJQY TFEB_HUMAN Increases Expression [16]
Receptor tyrosine-protein kinase erbB-3 (ERBB3) OTRSST0A ERBB3_HUMAN Increases Expression [7]
Ribosomal protein S6 kinase beta-1 (RPS6KB1) OTAELNGX KS6B1_HUMAN Decreases Phosphorylation [18]
Eukaryotic translation initiation factor 4B (EIF4B) OTE8TXA8 IF4B_HUMAN Decreases Phosphorylation [14]
G1/S-specific cyclin-D1 (CCND1) OT8HPTKJ CCND1_HUMAN Decreases Expression [15]
G1/S-specific cyclin-E1 (CCNE1) OTLD7UID CCNE1_HUMAN Decreases Expression [14]
Mitogen-activated protein kinase 3 (MAPK3) OTCYKGKO MK03_HUMAN Increases Activity [19]
Mitogen-activated protein kinase 1 (MAPK1) OTH85PI5 MK01_HUMAN Increases Activity [19]
RAC-alpha serine/threonine-protein kinase (AKT1) OT8H2YY7 AKT1_HUMAN Decreases Phosphorylation [10]
Cyclin-dependent kinase inhibitor 1 (CDKN1A) OTQWHCZE CDN1A_HUMAN Increases Expression [14]
Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform (PIK3CB) OTO8JQJA PK3CB_HUMAN Affects Activity [10]
Serine/threonine-protein kinase mTOR (MTOR) OTHH8KU7 MTOR_HUMAN Decreases Activity [20]
Caspase-3 (CASP3) OTIJRBE7 CASP3_HUMAN Increases Activity [21]
Cyclin-dependent kinase inhibitor 1B (CDKN1B) OTNY5LLZ CDN1B_HUMAN Increases Expression [14]
Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform (PIK3CG) OT3FAU4Y PK3CG_HUMAN Affects Activity [10]
Glycogen synthase kinase-3 beta (GSK3B) OTL3L14B GSK3B_HUMAN Decreases Phosphorylation [18]
Caspase-9 (CASP9) OTD4RFFG CASP9_HUMAN Increases Cleavage [12]
Small ribosomal subunit protein eS6 (RPS6) OTT4D1LN RS6_HUMAN Decreases Phosphorylation [17]
Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1) OT2YYI1A MCL1_HUMAN Decreases Expression [7]
Eukaryotic translation initiation factor 4E-binding protein 1 (EIF4EBP1) OTHBQVD5 4EBP1_HUMAN Decreases Phosphorylation [22]
Cyclin-G2 (CCNG2) OTII38K2 CCNG2_HUMAN Increases Expression [7]
Hypoxia-inducible factor 1-alpha (HIF1A) OTADSC03 HIF1A_HUMAN Decreases Expression [13]
Carbonic anhydrase 9 (CA9) OTNA51XT CAH9_HUMAN Decreases Expression [13]
Atos homolog protein A (ATOSA) OTWFM5G0 ATOSA_HUMAN Increases Expression [7]
Bcl2-associated agonist of cell death (BAD) OT63ERYM BAD_HUMAN Decreases Phosphorylation [22]
Proline-rich AKT1 substrate 1 (AKT1S1) OT4JHN4Y AKTS1_HUMAN Decreases Phosphorylation [23]
Serine/threonine-protein kinase Sgk3 (SGK3) OTQ6QO99 SGK3_HUMAN Decreases Phosphorylation [15]
Phosphoinositide-3-kinase-interacting protein 1 (PIK3IP1) OTWE5G4T P3IP1_HUMAN Increases Expression [7]
UDP-N-acetylglucosamine--peptide N-acetylglucosaminyltransferase 110 kDa subunit (OGT) OT1Z1ZXE OGT1_HUMAN Increases Response To Substance [24]
RNA cytidine acetyltransferase (NAT10) OT6JQO26 NAT10_HUMAN Affects Response To Substance [25]
GTPase KRas (KRAS) OT78QCN8 RASK_HUMAN Increases Response To Substance [7]
Epidermal growth factor receptor (EGFR) OTAPLO1S EGFR_HUMAN Increases Response To Substance [7]
ATP-dependent translocase ABCB1 (ABCB1) OTEJROBO MDR1_HUMAN Affects Transport [26]
Dendrin (DDN) OTM52ZF5 DEND_HUMAN Increases Response To Substance [24]
Receptor tyrosine-protein kinase erbB-2 (ERBB2) OTOAUNCK ERBB2_HUMAN Increases Response To Substance [27]
Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN (PTEN) OTOWDUNT PTEN_HUMAN Increases Response To Substance [23]
Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (PIK3CA) OTTOMI8J PK3CA_HUMAN Increases Response To Substance [27]
Pro-neuregulin-1, membrane-bound isoform (NRG1) OTZO6F1X NRG1_HUMAN Decreases Response To Substance [28]
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⏷ Show the Full List of 54 DOT(s)
Indication(s) of Cotellic
Disease Entry ICD 11 Status REF
Melanoma 2C30 Phase 3 [4]
Breast cancer 2C60-2C65 Phase 2 [5]
Head and neck cancer 2D42 Phase 1 [5]
Renal cell carcinoma 2C90 Phase 1 [5]
Solid tumour/cancer 2A00-2F9Z Phase 1 [6]
Urothelial carcinoma 2C92.0 Phase 1 [5]

References

1 ClinicalTrials.gov (NCT00996892) Safety, Tolerability and Pharmacokinetics of Cobimetinib in Combination With Pictilisib in Patients With Locally Advanced or Metastatic Solid Tumors
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 Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
5 Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
6 ClinicalTrials.gov (NCT01106599) A Study Evaluating the Safety, Tolerability, and Pharmacokinetics of GDC-0623 in Patients With Locally Advanced or Metastatic Solid Tumors. U.S. National Institutes of Health.
7 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.
8 Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov. 2009 Aug;8(8):627-44.
9 A multifactorial approach to hepatobiliary transporter assessment enables improved therapeutic compound development. Toxicol Sci. 2013 Nov;136(1):216-41.
10 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.
11 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.
12 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.
13 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.
14 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.
15 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.
16 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.
17 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.
18 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.
19 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.
20 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.
21 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.
22 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.
23 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.
24 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.
25 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.
26 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.
27 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.
28 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.