Details of the Drug Combination

General Information of Drug Combination (ID: DCU2M04)

• Drug Combination Name: HKI-272 + Temsirolimus
• Indication: HER2-mutant Non-Small Cell Lung Cancer; Status: Phase 2 [1]
• Component Drugs:
  HKI-272 (DM6QOVN): Small molecular drug
  Temsirolimus (DMS104F): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of HKI-272

Disease Entry	ICD 11	Status	REF
Breast cancer	2C60-2C65	Phase 3	[2]

HKI-272 Interacts with 4 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Erbb2 tyrosine kinase receptor (HER2)	TT6EO5L	ERBB2_HUMAN	Inhibitor	[4]
Epidermal growth factor receptor (EGFR)	TTGKNB4	EGFR_HUMAN	Inhibitor	[5]
Vascular endothelial growth factor receptor 2 (KDR)	TTUTJGQ	VGFR2_HUMAN	Inhibitor	[5]
ERBB2 messenger RNA (HER2 mRNA)	TTR5TV4	ERBB2_HUMAN	Inhibitor	[6]

HKI-272 Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[7]

HKI-272 Interacts with 3 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[8]
Inhibitor of nuclear factor kappa-B kinase subunit beta (IKBKB)	OT9RDS3H	IKKB_HUMAN	Decreases Expression	[9]
Epidermal growth factor receptor (EGFR)	OTAPLO1S	EGFR_HUMAN	Decreases Activity	[10]

Indication(s) of Temsirolimus

Disease Entry	ICD 11	Status	REF
Renal cell carcinoma	2C90	Approved	[3]

Temsirolimus Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Serine/threonine-protein kinase mTOR (mTOR)	TTCJG29	MTOR_HUMAN	Inhibitor	[11]

Temsirolimus Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[12]

Temsirolimus Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[13]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[13]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[13]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Breast Cancer	DCVRHD0	N. A.	Phase 1	[14]

References

• [1] ClinicalTrials.gov (NCT01827267) Neratinib With and Without Temsirolimus for Patients With HER2 Activating Mutations in Non-Small Cell Lung Cancer
• [2] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800021154)
• [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: 5892).
• [4] A comparison of physicochemical property profiles of marketed oral drugs and orally bioavailable anti-cancer protein kinase inhibitors in clinical development. Curr Top Med Chem. 2007;7(14):1408-22.
• [5] Dual irreversible kinase inhibitors: quinazoline-based inhibitors incorporating two independent reactive centers with each targeting different cyst... Bioorg Med Chem. 2007 Jun 1;15(11):3635-48.
• [6] Identification of genotype-correlated sensitivity to selective kinase inhibitors by using high-throughput tumor cell line profiling. Proc Natl Acad Sci U S A. 2007 Dec 11;104(50):19936-41.
• [7] Pharmacodynamics, pharmacokinetics and clinical efficacy of neratinib in HER2-positive breast cancer and breast cancer with HER2 mutations. Expert Opin Drug Metab Toxicol. 2016 Aug;12(8):947-57.
• [8] A multifactorial approach to hepatobiliary transporter assessment enables improved therapeutic compound development. Toxicol Sci. 2013 Nov;136(1):216-41.
• [9] Irreversible EGFR inhibitor EKB-569 targets low-LET -radiation-triggered rel orchestration and potentiates cell death in squamous cell carcinoma. PLoS One. 2011;6(12):e29705. doi: 10.1371/journal.pone.0029705. Epub 2011 Dec 29.
• [10] Cysteine mapping in conformationally distinct kinase nucleotide binding sites: application to the design of selective covalent inhibitors. J Med Chem. 2011 Mar 10;54(5):1347-55. doi: 10.1021/jm101396q. Epub 2011 Feb 15.
• [11] Advances in kinase targeting: current clinical use and clinical trials. Trends Pharmacol Sci. 2014 Nov;35(11):604-20.
• [12] Association of NR1I2, CYP3A5 and ABCB1 genetic polymorphisms with variability of temsirolimus pharmacokinetics and toxicity in patients with metastatic bladder cancer. Cancer Chemother Pharmacol. 2017 Sep;80(3):653-659.
• [13] Drug Interactions Flockhart Table
• [14] ClinicalTrials.gov (NCT01111825) Temsirolimus Plus Neratinib for Patients With Metastatic HER2-Amplified or Triple Negative Breast Cancer