A Phase I/II, Open-Label, Dose Ranging Study of the Safety, Tolerance, Pharmacokinetics and Potential Activity of HE3235 When Administered Orally to Patients With Prostate Cancer

This is a phase I/II, open-label, dose escalation study of HE3235 administered orally to patients with advanced prostate cancer who have failed hormone therapy and at least one taxane based chemotherapy regimen.

Start Date01 Jul 2008

Sponsor / Collaborator

Harbor Therapeutics, Inc.

100 Clinical Results associated with HE-3235

100 Translational Medicine associated with HE-3235

100 Patents (Medical) associated with HE-3235

Literatures (Medical) associated with HE-3235

01 Nov 2016·SteroidsQ4 · MEDICINE

Explorative study on the anticancer activity, selectivity and metabolic stability of related analogs of aminosteroid RM-133

Q4 · MEDICINE

Article

Author: Poirier, Donald ; Dutour, Raphaël ; Maltais, René ; Perreault, Martin

RM-133 is a key representative of a new family of aminosteroids reported as potent anticancer agents. Although RM-133 produced interesting results in 4 mouse xenograft cancer models when injected subcutaneously, it needs to be improved to increase its in vivo potency. Thus, to obtain an analog of RM-133 with a better drug potential, a structure-activity relationship study was conducted by synthesizing eleven RM-133-related compounds and addressing their antiproliferative activity on 3 human cancer cells (HL-60, OVCAR-3 and PANC-1) and 3 human normal cell lines (primary ovary, pancreas and renal proximal tubule) as well as their metabolic stability in human liver microsomes. When the 2β-tertiary amine of RM-133 was transformed into a salt or moved to position 3β, the anticancer activity was lost. Modifying the orientation of the side chain of RM-133 increased anticancer activity and selectivity, but led to a drastic loss of stability. The protection of the 3α-hydroxyl of RM-133 by the formation of an ester or a carbamate stabilized the molecule against the phase I metabolic enzymes without affecting its anticancer activity. In comparison to RM-133, the 3-dimethylcarbamate derivative 3 is more selective for cancer cells over normal cells and is much more stable in liver microsomes. Those results support the use of a pro-drug strategy targeting the 3α-hydroxyl of RM-133 as an approach to improve its drug properties. The work presented will enable the development of an optimized anticancer drug of the aminosteroid family that is suitable for a future phase I clinical trial.

01 Apr 2012·Bioorganic & Medicinal ChemistryQ3 · MEDICINE

Aglycone-focused randomization of 2-difluoromethylphenyl-type sialoside suicide substrates for neuraminidases

Q3 · MEDICINE

Article

Author: Hiroshi Hinou ; Shin-Ichiro Nishimura ; Hirokazu Kai

A selective and potent inhibitor of neuraminidases, a hydrolase that is responsible for processing sialylated glycoconjugates, is a promising drug candidate for various infective diseases. The current study demonstrates that the use of an aglycone-focused library of 2-difluoromethylphenyl α-sialosides is an effective technique to find potent and selective mechanism-based labeling reagents for neuraminidases. The focused library was constructed from a 4-azide-2-difluoromethylphenyl sialoside (2) and an alkyne-terminated compound library by a click reaction. The focused library showed different inhibition patterns for two neuraminidases, Vibrio cholerae neuraminidase (VCNA) and human neuraminidase 2 (hNeu2), and the most potent inhibitors for each neuraminidase were selected. A kinetic analysis of the selected inhibitors demonstrated that the modification of the aglycone moiety improved the K(I) value with little change in the t(1/2) value of the enzyme activity relative to the basic skeleton (2).

01 Feb 2012·Investigational New DrugsQ3 · MEDICINE

17α-Alkynyl 3α, 17β-androstanediol non-clinical and clinical pharmacology, pharmacokinetics and metabolism

Q3 · MEDICINE

Article

Author: Theodore Page ; David Bell ; Michael Kennedy ; Evelyn Delorme ; Clarence Ahlem ; Steven White ; Dwight Stickney ; Chris Reading ; James Frincke ; Sonia Villegas

17α-ethynyl-5α-androstane-3α, 17β-diol (HE3235, Apoptone) is an orally bioavailable synthetic analogue of 3β-androstanediol, that is active in rodent models of prostate and breast cancer, and is in Phase IIa clinical trials for the treatment of early- and late-stage prostate cancer. In preparation for clinical studies, nuclear hormone receptor and P450 interactions for HE3235 and major metabolites were characterized in vitro, and pharmacokinetics and metabolite profiles were studied in rodents, dogs, and monkeys. Four-week safety studies conducted in rats and dogs indicated a substantial margin of safety for clinical use, and no evidence of electrocardiographic or neurological effects, although anorexia, thrombocytopenia, and hypokalemia were identified as potentially dose-limiting toxicities at superpharmacological exposures. Pharmacokinetics and drug metabolism have been studied in prostate cancer patients.

100 Deals associated with HE-3235

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R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Advanced Prostate Carcinoma	Phase 2	United States	Harbor Therapeutics, Inc.	01 Jul 2008
Breast Cancer	Phase 2	United States	Harbor Therapeutics, Inc.	-
Prostatic Cancer	Phase 2	-	China State Institute of Pharmaceutical Industry	-
Prostatic Cancer	Phase 2	-	Harbor	-

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


ASCO2010	Phase 1/2	Castration-Resistant Prostatic Cancer	32	HE3235	(tckacnvhvz) = nvxigatnwa zezgjttkdv (lbibewidzm ) View more	-	20 May 2010

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