Details of the Drug

General Information of Drug (ID: DM3PVBJ)

• Drug Name: M2698
• Synonyms: HXAUJHZZPCBFPN-QGZVFWFLSA-N; 1379545-95-5; SCHEMBL15262358; EX-A1187; AKOS030627134; M2698(MSC-2363318A)

Indication

Disease Entry	ICD 11	Status	REF
Solid tumour/cancer	2A00-2F9Z	Phase 1	[1]

• #Ro5 Violations (Lipinski): 0:
  Molecular Weight (mw); 449.9
  Topological Polar Surface Area (xlogp); 3.9
  Rotatable Bond Count (rotbonds); 6
  Hydrogen Bond Donor Count (hbonddonor); 2
  Hydrogen Bond Acceptor Count (hbondacc); 8
• Chemical Identifiers:
  Formula: C21H19ClF3N5O
  IUPAC Name: 4-[[(1S)-2-(azetidin-1-yl)-1-[4-chloro-3-(trifluoromethyl)phenyl]ethyl]amino]quinazoline-8-carboxamide
  Canonical SMILES: C1CN(C1)C[C@H](C2=CC(=C(C=C2)Cl)C(F)(F)F)NC3=NC=NC4=C3C=CC=C4C(=O)N
  InChI: InChI=1S/C21H19ClF3N5O/c22-16-6-5-12(9-15(16)21(23,24)25)17(10-30-7-2-8-30)29-20-14-4-1-3-13(19(26)31)18(14)27-11-28-20/h1,3-6,9,11,17H,2,7-8,10H2,(H2,26,31)(H,27,28,29)/t17-/m1/s1
  InChIKey: HXAUJHZZPCBFPN-QGZVFWFLSA-N
• Cross-matching ID:
  PubChem CID: 89808643
  CAS Number: 1379545-95-5
  TTD ID: D06HYF

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
RAC-alpha serine/threonine-protein kinase (AKT1)	TTWTSCV	AKT1_HUMAN	Inhibitor	[1]
RAC-gamma serine/threonine-protein kinase (AKT3)	TTAZ05C	AKT3_HUMAN	Inhibitor	[1]
Ribosomal protein S6 kinase beta-1 (S6K1)	TTG0U4H	KS6B1_HUMAN	Inhibitor	[1]

Molecular Expression Atlas of This Drug

• The Studied Disease: Solid tumour/cancer
• ICD Disease Classification: 2A00-2F9Z

Molecule Name	Molecule Type	Gene Name	p-value	Fold-Change	Z-score
RAC-alpha serine/threonine-protein kinase (AKT1)	DTT	AKT1	2.63E-29	0.65	1.45
RAC-gamma serine/threonine-protein kinase (AKT3)	DTT	AKT3	6.79E-01	-0.02	-0.08

References

• [1] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [2] 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.
• [3] 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.
• [4] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [5] 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).
• [6] CenterWatch. Drugs in Clinical Trials Database. CenterWatch. 2008.
• [7] The novel AKT inhibitor afuresertib shows favorable safety, pharmacokinetics, and clinical activity in multiple myeloma. Blood. 2014 Oct 2;124(14):2190-5.
• [8] Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
• [9] First-in-man clinical trial of the oral pan-AKT inhibitor MK-2206 in patients with advanced solid tumors.J Clin Oncol.2011 Dec 10;29(35):4688-95.
• [10] Inhibiting the akt pathway in cancer treatment: three leading candidates. P T. 2011 Apr;36(4):225-7.
• [11] DOI: 10.1016/S1359-6349(10)71767-5
• [12] A first-in-human phase I trial of LY2780301, a dual p70 S6 kinase and Akt Inhibitor, in patients with advanced or metastatic cancer. Invest New Drugs. 2015 Jun;33(3):710-9.
• [13] Targeting the phosphoinositide 3-kinase (PI3K) pathway in cancer
• [14] Phase 0 clinical chemoprevention trial of the Akt inhibitor SR13668. Cancer Prev Res (Phila). 2011 Mar;4(3):347-53.
• [15] Phase I pharmacokinetic and pharmacodynamic study of triciribine phosphate monohydrate, a small-molecule inhibitor of AKT phosphorylation, in adult subjects with solid tumors containing activated AKT.Invest New Drugs.2011 Dec;29(6):1381-9.
• [16] Characterization of an Akt kinase inhibitor with potent pharmacodynamic and antitumor activity.Cancer Res.2008 Apr 1;68(7):2366-74.
• [17] Characterization of PF-4708671, a novel and highly specific inhibitor of p70 ribosomal S6 kinase (S6K1). Biochem J. 2010 Oct 15;431(2):245-55.
• [18] Ribosomal S6 kinase (RSK) modulators: a patent review.Expert Opin Ther Pat. 2016 Sep;26(9):1061-78.
• [19] Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J. 2000 Oct 1;351(Pt 1):95-105.
• [20] 4-arylazo-3,5-diamino-1H-pyrazole CDK inhibitors: SAR study, crystal structure in complex with CDK2, selectivity, and cellular effects. J Med Chem. 2006 Nov 2;49(22):6500-9.
• [21] Optimization of protein kinase CK2 inhibitors derived from 4,5,6,7-tetrabromobenzimidazole. J Med Chem. 2004 Dec 2;47(25):6239-47.