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851983-85-2 (TOK-001)

1

Identification

TOK-001 TOK-001
Name TOK-001
Formula C26H32N2O
MW 388.55
CAS No. 851983-85-2
EINECS
Smiles C[[email protected]@]12C(N3C=NC4=CC=CC=C34)=CC[[email protected]]1([[email protected]@]5(CC=C6[[email protected]@](C)([[email protected]]5(CC2)[H])CC[[email protected]@H](C6)O)[H])[H]
Synonyms VN/124-1; Galeterone; VN 124;TOK001;TOK 001; (3S,8R,9S,10R,13S,14S)-17-(1H-benzo[d]imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-3-ol
InChI InChI=1S/C26H32N2O/c1-25-13-11-18(29)15-17(25)7-8-19-20-9-10-24(26(20,2)14-12-21(19)25)28-16-27-22-5-3-4-6-23(22)28/h3-7,10,16,18-21,29H,8-9,11-15H2,1-2H3/t18-,19-,20-,21-,25-,26-/m0/s1
2

Introduction

TOK-001 (VN/124-1; Galeterone) is a multifunctional antiandrogen and CYP17 inhibitor(IC50=47 nM) in castration resistant prostate cancer (CRPC). IC50 value: 47 nM Target: CYP17 TOK-001 and abiraterone reduced AR protein and mRNA expression, and antagonized AR-dependent promoter activation induced by androgen.

Background Information

Galeterone (TOK-001, VN/124-1) is a selective CYP17 inhibitor and androgen receptor (AR) antagonist with IC50 of 300 nM and 384 nM, respectively. Galeterone is effective at preventing binding of [3H]-R1881 (methyltrienolone, a stable synthetic androgen) to both the mutant AR (T877A) in LNCaP cells and the wild-type AR in PC-3AR cells. Galeterone potently inhibits the AR-mediated transcription in LNCaP cells transiently transfected with a probasin luciferase reporter construct AARZ-Luc in a concentration-dependent manner. Galeterone inhibits the growth of DHT-stimulated LNCaP and LAPC4 prostate cancer cells with IC50 of <10 μM. Galeterone is very effective at inhibiting the growth of androgen-dependent LAPC4 human prostate tumor xenograft. In the LAPC4 xenograft, Galeterone is a more potent agent in reducing tumor growth than other compounds (VN/85, VN/87, and VN108) and is more effective than castration and casodex. Treatment with Galeterone markedly reduces AR protein levels both in vivo and in vitro. Thus, Galeterone disrupts androgen receptor (AR) signaling via a novel triple mechanism of action (CYP17 inhibition, competitive inhibition, and down-regulation of the AR). Galeterone also inhibits the growth of androgen-independent prostate cancer cells via induction of the endoplasmic reticulum stress response. Additionally, Galeterone in combination with thapsigargin exhibits synergistic effect in inhibiting PC-3 cell growth. Galeterone in combination with everolimus or gefitinib demonstrates superior synergy for growth inhibition against hormone-refractory prostate cancer cell line (high-passage LNCaP, HP-LNCaP) compared with bicalutamide. Dual inhibition of AR and mTOR with Galeterone and everolimus acts in concert to reduce tumor growth rates in the castration-resistant prostate cancer xenograft model. Galeterone is a superior inhibitor than abiraterone of R1881-induced transcriptional activity of both wild type and mutant AR. ......by AbMole BioScience
TOK-001 (Galeterone) is both an androgen receptor antagonist and CYP17A1 inhibitor. ......by AdooQ BioScience, LLC
Description ......by Apexbio Technology LLC
Galeterone?(TOK-001?or?VN/124-1) is a novel?antiandrogen?under development by?Tokai Pharmaceuticals?for the treatment of?prostate cancer. It possesses a unique dual?mechanism of action, acting as both anandrogen receptor?antagonist?and an?inhibitor?of?CYP ......by BOC Sciences
TOK-001 is a multifunctional antiandrogen and CYP17 inhibitor (IC50=47 nM) in castration resistant prostate cancer (CRPC). ......by MedChemexpress Co., Ltd.
Galeterone, also known as TOK-001 and NX41765; is an orally bioavailable small-molecule androgen receptor modulator and CYP17 lyase inhibitor with potential antiandrogen activity. Galeterone exhibits three distinct mechanisms of action: 1) as an androgen receptor antagonist, 2) as a CYP17 lyase inhibitor and 3) by decreasing overall androgen receptor levels in prostate cancer tumors, all of which may result in a decrease in androgen-dependent growth signaling. ......by MedKoo Biosciences, Inc.
A potent 17α-hydroxylase/17,20-lyase (CYP17) inhibitor with IC50 of 300 nM; also shown to be potent pure AR antagonist; inhibits the growth of DHT-stimulated LNCaP and LAPC4 prostate cancer cells with IC50 <10 uM; causes marked down-regulation of AR protein expression, more efficacious than castration in the LAPC4 xenograft model.Prostate CancerPhase 3 Clinical ......by ProbeChem
Galeterone is a selective CYP17 inhibitor and androgen receptor (AR) antagonist with IC50 of 300 nM and 384 nM, respectively, and is a potent inhibitor of human prostate tumor growth. Phase 2. ......by Selleck Chemicals LLC
Galeterone is a selective CYP17 inhibitor and androgen receptor (AR) antagonist with IC50 of 300 nM and 384 nM, respectively, and is a potent inhibitor of human prostate tumor growth. Phase 2. ......by Target Molecule Corp.
CYP17 inhibitor (IC50 = 300 nM) and androgen receptor antagonist (IC50 = 384 nM in PC3-AR cells). Inhibits DHT-stimulated prostate cancer cell proliferation in vitro. Exhibits antitumor activity in SCID mice bearing prostate cancer xenografts. ......by Tocris Bioscience Inc.
3

Protocol(Only for Reference)

Cell Experiment

Animal Experiment

Animal Models Male severe combined immunodeficient (SCID) mice inoculated subcutaneously (s.c.) with LAPC4 cells
Dosage 50 mg/kg
Formulation Prepared at 17.2 mg/mL in a 0.3% solution of hydroxypropyl cellulose in saline
Administration Injection s.c. twice daily
Source Selleck Chemicals LLC
4

Physical and Chemical Properties

Appearance:White to off-white solid EBNumber:EB000028832

Storage condition

Solubility

DMSO by MedChemexpress Co., Ltd.
(25°C) * In vitro DMSO 24 mg/mL (61.76 mM); Ethanol40 mg/mL warming (102.94 mM); Water<1 mg/mL (<1 mM); In vivo 0.5% hydroxyethyl cellulose30 mg/mL by Selleck Chemicals LLC
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Mechanism and Indication

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Clinical Information

Product Name Sponsor & Collaborators Indications Start Date End Date Phase
TOK-001 Tokai Pharmaceuticals Inc Hormone refractory prostate cancer 2012/12/31 2014/9/30 Phase 2 Clinical
TOK-001 Tokai Pharmaceuticals Inc Hormone refractory prostate cancer 2009/10/31 2012/8/31 Phase 1 Clinical
TOK-001 - Phase 3
7

Safety Data of TOK-001

8

Spectral Information

9

Suppliers List

Company Price and Availability Country/Region
AA Blocks LLC
AbMole BioScience USA
AdooQ BioScience, LLC USA
Apexbio Technology LLC USA
Ark Pharm, Inc. USA
BLD Pharmatech
BOC Sciences
Biochempartner Co., Ltd China
CHEMSCENE, LLC 5mg/USD60();10mg/USD90() USA
Cayman Chemical Company USA
MedChemexpress Co., Ltd. 5mg/USD60();10mg/USD90() USA
MedKoo Biosciences, Inc. USA
ProbeChem
Pure Chemistry Scientific Inc. 5mg/USDnull(In stock) USA
Selleck Chemicals LLC 5mg/USD170(In stock);10mM/1mLIn DMSO/USD260(In stock);25mg/USD470(In stock);50mg/USD670(In stock);200mg/USD1670(In stock) USA
Shanghai Haoyuan Chemexpress Co., Ltd. 5mg/USD60();10mg/USD90() China
Target Molecule Corp. 5mg/USD97();10mg/USD171();50mg/USD528() USA
Tocris Bioscience Inc. USA
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Other Forms of 851983-85-2

Name CAS No Formula MW

Recommended Compounds in Cytochrome P450

Name CAS No Formula MW
Dafadine-A 1065506-69-5 C23H25N3O3 391.46
VT-464 (racemate) 1375603-36-3 C18H17F4N3O3 399.34
VT-464 1610537-15-9 C18H17F4N3O3 399.34
Isosilybin 72581-71-6 C25H22O10 482.44
Memantine (hydrochloride) 41100-52-1 C12H22ClN 215.76
Clarithromycin 81103-11-9 C38H69NO13 747.95
(+)-Ketoconazole 142128-59-4 C26H28Cl2N4O4 531.43
(+)-Ketoconazole 142128-59-4 C26H28Cl2N4O4 531.4309
Galangin 548-83-4
Bergapten 484-20-8 C12H8O4 216.19
Naringin 10236-47-2 C27H32O14 580.53
Diosmetin 520-34-3 C16H12O6 300.26
Fenofibrate 49562-28-9 C20H21ClO4 360.83
Bergaptol 486-60-2 C11H6O4 202.1629
Talarozole (R enantiomer) 870093-23-5 C21H23N5S 377.5058
Choline Fenofibrate 856676-23-8 C22H28ClNO5 421.91
Talarozole 201410-53-9 C21H23N5S 377.51
Isavuconazole 241479-67-4 C22H17F2N5OS 437.4650864
Cobicistat 1004316-88-4 C40H53N7O5S2 776.02
Methoxsalen 298-81-7 C12H8O4 216.19

Recommended Compounds in Same Indication

Name CAS No Formula MW
TAK-700 (R-form) 752243-39-3 C18H17N3O2 307.35
Olaparib 763113-22-0 C24H23FN4O3 434.46
KX2-391 897016-82-9 C26H29N3O3 431.53
Bicalutamide 90357-06-5 C18H14F4N2O4S 430.37
Enzalutamide 915087-33-1 C21H16F4N4O2S 464.44
Linsitinib 867160-71-2 C26H23N5O 421.49
Fenretinide 65646-68-6 C26H33NO2 391.55
Retaspimycin 857402-23-4 C31H45N3O8 587.7
Retaspimycin (Hydrochloride) 857402-63-2 C31H46ClN3O8 624.17
Bafetinib 859212-16-1 C30H31F3N8O 576.6154
AT13387 912999-49-6 C24H31N3O3 409.52
Tasquinimod 254964-60-8 C20H17F3N2O4 406.36
Orteronel 566939-85-3 C18H17N3O2 307.35
Orteronel (racemate) 426219-18-3 C18H17N3O2 307.3465
TAK-700 (salt) 426219-53-6 C28H28N4O7 532.54
Cabozantinib 849217-68-1 C28H24FN3O5 501.51
Odanacatib 603139-19-1 C25H27F4N3O3S 525.56
Zibotentan 186497-07-4 C19H16N6O4S 424.43
Danusertib 827318-97-8 C26H30N6O3 474.55
Atrasentan 173937-91-2 C29H38N2O6 510.62
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Route of Synthesis

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References

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More Information

TOK-001

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