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
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
| 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
Edited
Sat Dec 16 11:42:30 UTC 2023
by
admin
on
Sat Dec 16 11:42:30 UTC 2023
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| Record UNII |
2H36UAA53E
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| Record Status |
Validated (UNII)
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| Record Version |
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-
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1246203-32-6
Created by
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46917355
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2H36UAA53E
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DTXSID70677349
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782362
Created by
admin on Sat Dec 16 11:42:30 UTC 2023 , Edited by admin on Sat Dec 16 11:42:30 UTC 2023
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TARGET -> INHIBITOR |
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TARGET -> INHIBITOR |
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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
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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
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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.
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