Details of the Drug-Related molecule(s) Interaction Atlas

General Information of Drug (ID: DM5H0R9)

• Drug Name: Enzastaurin Drug Info
• Synonyms: LY317615; LE-0014; LY317615, Enzastaurin; 3-(1-methyl-1H-indol-3-yl)-4-{1-[1-(pyridin-2-ylmethyl)piperidin-4-yl]-1H-indol-3-yl}-1H-pyrrole-2,5-dione; 3-(1-methylindol-3-yl)-4-[1-[1-(pyridin-2-ylmethyl)piperidin-4-yl]indol-3-yl]pyrrole-2,5-dione

Indication

Disease Entry	ICD 11	Status	REF
Diffuse large B-cell lymphoma	2A81	Phase 3	[1]
Non-hodgkin lymphoma	2B33.5	Phase 3	[2] , [3] , [4]
Glioblastoma multiforme	2A00.0	Phase 2	[2] , [4]
Central nervous system disease	8A04-8D87	Phase 1	[2] , [4]

• Therapeutic Class: Anticancer Agents
• Cross-matching ID:
  PubChem CID: 176167
  ChEBI ID: CHEBI:91368
  CAS Number: CAS 170364-57-5
  TTD Drug ID: DM5H0R9
  INTEDE Drug ID: DR1898

Molecule-Related Drug Atlas

Drug(s) Metabolized By Cytochrome P450 3A4 (CYP3A4)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Doxorubicin	DMVP5YE	Solid tumour/cancer	2A00-2F9Z	Approved	[6]
Progesterone	DMUY35B	Premature labour	JB00	Approved	[7]
Tamoxifen	DMLB0EZ	Breast cancer	2C60-2C65	Approved	[8]
Estradiol	DMUNTE3	Breast cancer	2C60-2C65	Approved	[9]
Acetaminophen	DMUIE76	Pain	MG30-MG3Z	Approved	[10]
Imatinib	DM7RJXL	Acute lymphoblastic leukaemia	2A85	Approved	[11]
Etoposide	DMNH3PG	Solid tumour/cancer	2A00-2F9Z	Approved	[12]
Zidovudine	DM4KI7O	Human immunodeficiency virus infection	1C62	Approved	[13]
Prasterone	DM67VKL	Chronic obstructive pulmonary disease	CA22	Approved	[7]
Verapamil	DMA7PEW	Hypertension	BA00-BA04	Approved	[14]

Drug(s) Targeting Protein kinase C beta (PRKCB)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
RUBOXISTAURIN HYDROCHLORIDE	DMQOCD8	Lymphoma	2A80-2A86	Phase 3	[15]
Sotrastaurin acetate	DME53YS	Renal transplantation	NE84	Phase 2	[16]
LY333531	DMGMC8H	Solid tumour/cancer	2A00-2F9Z	Phase 2	[17]
MS-553	DM7ER9J	Chronic lymphocytic leukaemia	2A82.0	Phase 1	[18]
Linetastine	DMF8B62	Rhinitis	FA20	Discontinued in Phase 2	[19]
BALANOL	DMDLN9E	N. A.	N. A.	Terminated	[20]
RO-320432	DMFZ1YW	N. A.	N. A.	Terminated	[21]
LY-317644	DMM20PI	N. A.	N. A.	Terminated	[22]
RO-316233	DMAGLPW	Discovery agent	N.A.	Investigative	[23]
LY-326449	DMN53M4	Discovery agent	N.A.	Investigative	[24]

Drug(s) Targeting RAC-alpha serine/threonine-protein kinase (AKT1)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
AZD5363	DM9SKW8	Triple negative breast cancer	2C60-2C65	Phase 3	[1]
GDC-0068	DMWBZJD	Breast cancer	2C60-2C65	Phase 3	[1]
CI-1033	DMSI8N3	Lymphoma	2A80-2A86	Phase 2	[25]
CMX-2043	DMPSCVY	Cardiac disease	BA00-BE2Z	Phase 2	[26]
ARQ 092	DM5WK0J	Proteus syndrome	LD2C	Phase 2	[27]
GSK2110183	DMZHB37	leukaemia	2A60-2B33	Phase 2	[28]
RX-0201	DMTBAV3	Pancreatic cancer	2C10	Phase 2	[29]
Trametinib + 2141795	DMYP7TO	Solid tumour/cancer	2A00-2F9Z	Phase 2	[28]
PTX-200	DM0ZIT2	Breast cancer	2C60-2C65	Phase 2	[1]
Triciribine prodrug	DMBN1XS	Solid tumour/cancer	2A00-2F9Z	Phase 1/2	[28]

Drug(s) Targeting PI3-kinase gamma (PIK3CG)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Bay 80-6946	DMLOS5R	Follicular lymphoma	2A80	Approved	[30]
IPI-145	DMWA24P	Follicular lymphoma	2A80	Approved	[31]
Buparlisib	DM1WEHC	Breast cancer	2C60-2C65	Phase 3	[32]
Rigosertib	DMOSTXF	Myelodysplastic syndrome	2A37	Phase 3	[33]
GDC-0032	DMT4QHD	Breast cancer	2C60-2C65	Phase 3	[1]
PQR309	DMMCYZ8	Squamous head and neck cell carcinom	2D60.0	Phase 2	[34]
SAR245409	DMQM7IL	Solid tumour/cancer	2A00-2F9Z	Phase 2	[35]
Xl147	DMML7BE	Solid tumour/cancer	2A00-2F9Z	Phase 2	[35]
SF1126	DML10K3	Head and neck cancer	2D42	Phase 2	[36]
PF-05212384	DMBL3VD	Solid tumour/cancer	2A00-2F9Z	Phase 2	[37]

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
PI3-kinase gamma (PIK3CG)	TTHBTOP	PK3CG_HUMAN	Inhibitor	[1]
Protein kinase C beta (PRKCB)	TTYPXQF	KPCB_HUMAN	Modulator	[3]
RAC-alpha serine/threonine-protein kinase (AKT1)	TTWTSCV	AKT1_HUMAN	Inhibitor	[1]

Drug-Metabolizing Enzyme (DME)

DME Name	DME ID	UniProt ID	MOA	REF
Cytochrome P450 3A4 (CYP3A4) Main DME	DE4LYSA	CP3A4_HUMAN	Substrate	[5]

References

• [1] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [2] 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: 5693).
• [3] The oral protein-kinase C beta inhibitor enzastaurin (LY317615) suppresses signalling through the AKT pathway, inhibits proliferation and induces apoptosis in multiple myeloma cell lines. Leuk Lymphoma. 2008 Jul;49(7):1374-83.
• [4] Emerging therapies for multiple myeloma. Expert Opin Emerg Drugs. 2009 Mar;14(1):99-127.
• [5] Phase I study of enzastaurin and bevacizumab in patients with advanced cancer: safety, efficacy and pharmacokinetics. Invest New Drugs. 2013 Jun;31(3):653-60.
• [6] Expression levels and activation of a PXR variant are directly related to drug resistance in osteosarcoma cell lines. Cancer. 2007 Mar 1;109(5):957-65.
• [7] Contribution of human hepatic cytochrome P450 isoforms to regioselective hydroxylation of steroid hormones. Xenobiotica. 1998 Jun;28(6):539-47.
• [8] Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: prominent roles for CYP3A and CYP2D6. J Pharmacol Exp Ther. 2004 Sep;310(3):1062-75.
• [9] Isoform-specific regulation of cytochromes P450 expression by estradiol and progesterone. Drug Metab Dispos. 2013 Feb;41(2):263-9.
• [10] Metabolic interactions between acetaminophen (paracetamol) and two flavonoids, luteolin and quercetin, through in-vitro inhibition studies. J Pharm Pharmacol. 2017 Dec;69(12):1762-1772.
• [11] Potent mechanism-based inhibition of CYP3A4 by imatinib explains its liability to interact with CYP3A4 substrates. Br J Pharmacol. 2012 Apr;165(8):2787-98.
• [12] Effects of morin on the pharmacokinetics of etoposide in rats. Biopharm Drug Dispos. 2007 Apr;28(3):151-6.
• [13] The metabolism of zidovudine by human liver microsomes in vitro: formation of 3'-amino-3'-deoxythymidine. Biochem Pharmacol. 1994 Jul 19;48(2):267-76.
• [14] Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675.
• [15] Ruboxistaurin: LY 333531. Drugs R D. 2007;8(3):193-9.
• [16] Emerging drugs for psoriasis. Expert Opin Emerg Drugs. 2009 Mar;14(1):145-63.
• [17] Protein kinase C beta inhibition attenuates the progression of experimental diabetic nephropathy in the presence of continued hypertension. Diabetes. 2003 Feb;52(2):512-8.
• [18] ClinicalTrials.gov (NCT03492125) A Study Of The Selective PKC-beta Inhibitor MS- 553. U.S. National Institutes of Health.
• [19] Potential new medical therapies for diabetic retinopathy: protein kinase C inhibitors. Am J Ophthalmol. 2002 May;133(5):693-8.
• [20] Evaluation of differential hypoxic cytotoxicity and electrochemical studies of nitro 5-deazaflavins, Bioorg. Med. Chem. Lett. 5(18):2155-2160 (1995).
• [21] Bisindolylmaleimide inhibitors of protein kinase C. Further conformational restriction of a tertiary amine side chain, Bioorg. Med. Chem. Lett. 4(11):1303-1308 (1994).
• [22] Synthesis of bisindolylmaleimide macrocycles, Bioorg. Med. Chem. Lett. 5(18):2093-2096 (1995).
• [23] Inhibitors of protein kinase C. 1. 2,3-Bisarylmaleimides. J Med Chem. 1992 Jan;35(1):177-84.
• [24] (S)-13-[(dimethylamino)methyl]-10,11,14,15-tetrahydro-4,9:16, 21-dimetheno-1H, 13H-dibenzo[e,k]pyrrolo[3,4-h][1,4,13]oxadiazacyclohexadecene-1,3(2H... J Med Chem. 1996 Jul 5;39(14):2664-71.
• [25] 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.
• [26] Pre-clinical and Clinical Safety Studies of CMX-2043: a cytoprotective lipoic acid analogue for ischaemia-reperfusion injury. Basic Clin Pharmacol Toxicol. 2014 Nov;115(5):456-64.
• [27] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [28] 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. (Target id: 1479).
• [29] CenterWatch. Drugs in Clinical Trials Database. CenterWatch. 2008.
• [30] BAY 80-6946 is a highly selective intravenous PI3K inhibitor with potent p110 and p110 activities in tumor cell lines and xenograft models.Mol Cancer Ther.2013 Nov;12(11):2319-30.
• [31] PI3K-delta and PI3K-gamma inhibition by IPI-145 abrogates immune responses and suppresses activity in autoimmune and inflammatory disease models. Chem Biol. 2013 Nov 21;20(11):1364-74.
• [32] Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov. 2009 Aug;8(8):627-44.
• [33] Phase I study of oral rigosertib (ON 01910.Na), a dual inhibitor of the PI3K and Plk1 pathways, in adult patients with advanced solid malignancies. Clin Cancer Res. 2014 Mar 15;20(6):1656-65.
• [34] 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. (Target id: 2155).
• [35] 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. (Target id: 2156).
• [36] An integrin-targeted, pan-isoform, phosphoinositide-3 kinase inhibitor, SF1126, has activity against multiple myeloma in vivo.Cancer Chemother Pharmacol.2013 Apr;71(4):867-81.
• [37] First-in-Human Study of PF-05212384 (PKI-587), a Small-Molecule, Intravenous, Dual Inhibitor of PI3K and mTOR in Patients with Advanced Cancer. Clin Cancer Res. 2015 Apr 15;21(8):1888-95.