U.S. Department of Health & Human Services Divider Arrow National Institutes of Health Divider Arrow NCATS

Details

Stereochemistry ACHIRAL
Molecular Formula C26H30F2N8O4S
Molecular Weight 588.629
Optical Activity NONE
Defined Stereocenters 0 / 0
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of VDC-597

SMILES

COC1=C2N=C(C(F)F)N(C2=CC=C1)C3=NC(=NC(=N3)N4CCOCC4)C5=CC=C(NS(=O)(=O)CCN(C)C)C=C5

InChI

InChIKey=GDCJHDUWWAKBIW-UHFFFAOYSA-N
InChI=1S/C26H30F2N8O4S/c1-34(2)13-16-41(37,38)33-18-9-7-17(8-10-18)23-30-25(35-11-14-40-15-12-35)32-26(31-23)36-19-5-4-6-20(39-3)21(19)29-24(36)22(27)28/h4-10,22,33H,11-16H2,1-3H3

HIDE SMILES / InChI

Molecular Formula C26H30F2N8O4S
Molecular Weight 588.629
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry No
Defined Stereocenters 0 / 0
E/Z Centers 0
Optical Activity NONE

Approval Year

Substance Class Chemical
Created
by admin
on Sat Dec 16 11:42:30 GMT 2023
Edited
by admin
on Sat Dec 16 11:42:30 GMT 2023
Record UNII
2H36UAA53E
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
VDC-597
Common Name English
SN-33597
Code English
ETHANESULFONAMIDE, N-(4-(4-(2-(DIFLUOROMETHYL)-4-METHOXY-1H-BENZIMIDAZOL-1-YL)-6-(4-MORPHOLINYL)-1,3,5-TRIAZIN-2-YL)PHENYL)-2-(DIMETHYLAMINO)-
Systematic Name English
PWT-33597
Code English
N-(4-(4-(2-(DIFLUOROMETHYL)-4-METHOXY-1H-BENZIMIDAZOL-1-YL)-6-(4-MORPHOLINYL)-1,3,5-TRIAZIN-2-YL)PHENYL)-2-(DIMETHYLAMINO)ETHANESULFONAMIDE
Systematic Name English
NSC-782362
Code English
Code System Code Type Description
CAS
1246203-32-6
Created by admin on Sat Dec 16 11:42:30 GMT 2023 , Edited by admin on Sat Dec 16 11:42:30 GMT 2023
PRIMARY
PUBCHEM
46917355
Created by admin on Sat Dec 16 11:42:30 GMT 2023 , Edited by admin on Sat Dec 16 11:42:30 GMT 2023
PRIMARY
FDA UNII
2H36UAA53E
Created by admin on Sat Dec 16 11:42:30 GMT 2023 , Edited by admin on Sat Dec 16 11:42:30 GMT 2023
PRIMARY
EPA CompTox
DTXSID70677349
Created by admin on Sat Dec 16 11:42:30 GMT 2023 , Edited by admin on Sat Dec 16 11:42:30 GMT 2023
PRIMARY
NSC
782362
Created by admin on Sat Dec 16 11:42:30 GMT 2023 , Edited by admin on Sat Dec 16 11:42:30 GMT 2023
PRIMARY
Related Record Type Details
ACTIVE MOIETY
VDC-597 (formerly PWT33597); Company: VetDC Inc.; Description: Dual inhibitor of Phosphoinositide 3-kinase (PI3K) alpha and mammalian target of rapamycin (mTOR, FRAP, RAFT1); Molecular Target: Phosphoinositide 3-kinase (PI3K) alpha, Mammalian target of rapamycin (mTOR) (FRAP) (RAFT1); Mechanism of Action: Mammalian target of rapamycin (mTOR) kinase inhibitor, Phosphoinositide 3-kinase (PI3K) alpha inhibitor; Therapeutic Modality: Small molecule; Latest Stage of Development: Phase I; Standard Indication: Solid tumors; Indication Details: Treat advanced solid tumors
ACTIVE MOIETY
Originator: Pathway Therapeutics; Class: Antineoplastic; Mechanism of Action: MTOR protein inhibitors, Phosphatidylinositol 3 kinase alpha inhibitor; Orphan Drug Status: No; On Fast track: No; Highest Development Phase: Phase I for Solid tumours; Most Recent Events: 14 Nov 2011 Pharmacodynamics data from a preclinical trial in Cancer presented at the 23rd AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics (AACR-NCI-EORTC), 01 Jun 2011 Phase-I clinical trials in Solid tumours in USA (PO), 25 May 2011 US FDA accepts an IND application for PWT 33597 in Solid tumours
ACTIVE MOIETY
We report here the design, discovery and characterization of PWT33597 (VDC-597), a dual inhibitor of PI3K alpha and mTOR, which entered human clinical trials in 2011. Starting with the known pan-Class I PI3-kinase inhibitor ZSTK474, we identified the methanesulfonylpiperazine analogue, 2-(difluoromethyl)-1-(4-(4-(methylsulfonyl)-1-piperazinyl)-6-(4-morpholinyl)-1,3,5-triazin-2-yl)-1H-benzimidazole as a promising lead compound with activity against both PI3K alpha (IC50 = 21 nM) and PI3K delta (IC50 = 18 nM). The addition of a methoxy group at the 4-position of the benzimidazole group led to a more selective inhibitor of PI3K alpha (IC50 = 6 nM versus 41 nM for PI3K delta), although with reduced solubility. A search for more soluble analogues identified SN 32976 as a selective inhibitor of PI3K alpha (IC50 = 28 nM) over both PI3K delta (IC50 = 287 nM) and mTOR (IC50 = 227 nM), with good aqueous solubility. SN 32976 displayed good oral bioavailability and was significantly more active than ZSTK474 against a U87 MG human tumor xenograft model in mice. A search for more metabolically stable analogues subsequently identified PWT33597, which maintained the selectivity for PI3K alpha (IC50 = 26 nM) over PI3K delta (IC50 = 291 nM) but now also displayed activity against mTOR in biochemical assays (IC50 = 21 nM). PWT33597 had good pharmacokinetic properties in multiple preclinical species, was not extensively metabolized in vivo and showed little potential for interaction with cytochrome P450 enzymes.