TH-302
Encyclopedia
TH-302 is an experimental cancer treatment
that is in clinical development at Threshold Pharmaceuticals, Inc. It is activated only at very low levels of oxygen
(hypoxia
). Such levels are common in human solid tumor
s, a phenomenon known as tumor hypoxia
. TH-302 exploits the activation of a nitroazole prodrug
by a process that involves a one electron reduction mediated by ubiquitous cellular reductases such as the NADPH cytochrome P450 to generate a radical anion prodrug (RP). In the presence of oxygen (normoxia) the radical anion prodrug reacts rapidly with oxygen to generate the original prodrug and superoxide
(SO). Under the low oxygen conditions of the hypoxic zones in tumors, however, the radical anion prodrug undergoes further irreversible reductions to the hydroxylamine
(HA) followed by elimination, releasing the active drug and an azole
derivative (AZ). This activation pathway is shown schematically below:
Phosphoramidate
-based, DNA-crosslinking, bis-alkylator mustards have long been used successfully in cancer chemotherapy and include the prodrugs ifosfamide
and cyclophosphamide
. To demonstrate that known drugs of proven efficacy could serve as the basis of efficacious hypoxia activated prodrugs, the 2-nitroimidizole HAP of the active phosphoramidate bis-alkylator derived from ifosfamide was synthesized. The resulting compound, TH-281, had a high HCR (hypoxia cytotoxicity ratio), a quantitative assessment of its hypoxia selectivity. Subsequent structure-activity relationship
(SAR) studies at Threshold showed that replacement of the chlorines in the alkylator portion of the prodrug with bromines improved potency about 10-fold. The final compound is TH-302.
TH-302 started a Phase 1
clinical trial in 2007 in various solid tumors. The Phase 1 trial is a multi-center, open-label, dose-escalation study in patients with solid tumor cancers. The primary objectives of the study are to determine the maximum tolerated dose (MTD) and dose-limiting toxicities of TH-302 in patients with advanced solid tumors and to establish the appropriate dose to be tested in Phase 2
clinical trials. The secondary objectives of the trial include establishing the pharmacokinetics
and assessing the anti-tumor activity of TH-302, as measured by objective response rate and duration of response, and to characterize the safety profile. Tumors will be evaluated at baseline and every eight weeks using the Response Evaluation Criteria In Solid Tumors (RECIST) criteria.
Experimental cancer treatment
Experimental cancer treatments are medical therapies intended or claimed to treat cancer by improving on, supplementing or replacing conventional methods ....
that is in clinical development at Threshold Pharmaceuticals, Inc. It is activated only at very low levels of oxygen
Oxygen
Oxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...
(hypoxia
Hypoxia (medical)
Hypoxia, or hypoxiation, is a pathological condition in which the body as a whole or a region of the body is deprived of adequate oxygen supply. Variations in arterial oxygen concentrations can be part of the normal physiology, for example, during strenuous physical exercise...
). Such levels are common in human solid tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
s, a phenomenon known as tumor hypoxia
Tumor hypoxia
Tumor hypoxia is the situation where tumor cells have been deprived of oxygen. As a tumor grows, it rapidly outgrows its blood supply, leaving portions of the tumor with regions where the oxygen concentration is significantly lower than in healthy tissues...
. TH-302 exploits the activation of a nitroazole prodrug
Prodrug
A prodrug is a pharmacological substance administered in an inactive form. Once administered, the prodrug is metabolised in vivo into an active metabolite, a process termed bioactivation. The rationale behind the use of a prodrug is generally for absorption, distribution, metabolism, and...
by a process that involves a one electron reduction mediated by ubiquitous cellular reductases such as the NADPH cytochrome P450 to generate a radical anion prodrug (RP). In the presence of oxygen (normoxia) the radical anion prodrug reacts rapidly with oxygen to generate the original prodrug and superoxide
Superoxide
A superoxide, also known by the obsolete name hyperoxide, is a compound that possesses the superoxide anion with the chemical formula O2−. The systematic name of the anion is dioxide. It is important as the product of the one-electron reduction of dioxygen O2, which occurs widely in nature...
(SO). Under the low oxygen conditions of the hypoxic zones in tumors, however, the radical anion prodrug undergoes further irreversible reductions to the hydroxylamine
Hydroxylamine
Hydroxylamine is an inorganic compound with the formula NH2OH. The pure material is a white, unstable crystalline, hygroscopic compound. However, hydroxylamine is almost always provided and used as an aqueous solution. It is used to prepare oximes, an important functional group. It is also an...
(HA) followed by elimination, releasing the active drug and an azole
Azole
An azole is a class of five-membered nitrogen heterocyclic ring compounds containing at least one other non-carbon atom of either nitrogen, sulfur, or oxygen. The parent compounds are aromatic and have two double bonds; there are successively reduced analogs with fewer...
derivative (AZ). This activation pathway is shown schematically below:
Phosphoramidate
Phosphoramidate
A phosphoramidate is a phosphate that has an NR2 instead of an OH group. The structure of phosphoramidic acid , 2PONH2, is present in PubChem....
-based, DNA-crosslinking, bis-alkylator mustards have long been used successfully in cancer chemotherapy and include the prodrugs ifosfamide
Ifosfamide
Ifosfamide is a nitrogen mustard alkylating agent used in the treatment of cancer.It is sometimes abbreviated "IFO".-Uses:It is given as a treatment for a variety of cancers, including:...
and cyclophosphamide
Cyclophosphamide
Cyclophosphamide , also known as cytophosphane, is a nitrogen mustard alkylating agent, from the oxazophorines group....
. To demonstrate that known drugs of proven efficacy could serve as the basis of efficacious hypoxia activated prodrugs, the 2-nitroimidizole HAP of the active phosphoramidate bis-alkylator derived from ifosfamide was synthesized. The resulting compound, TH-281, had a high HCR (hypoxia cytotoxicity ratio), a quantitative assessment of its hypoxia selectivity. Subsequent structure-activity relationship
Structure-activity relationship
The structure–activity relationship is the relationship between the chemical or 3D structure of a molecule and its biological activity. The analysis of SAR enables the determination of the chemical groups responsible for evoking a target biological effect in the organism...
(SAR) studies at Threshold showed that replacement of the chlorines in the alkylator portion of the prodrug with bromines improved potency about 10-fold. The final compound is TH-302.
TH-302 started a Phase 1
Phase 1
Phase 1, Phase I or Phase One may refer to:*Phase I of a clinical trial in medicine*Phase I reaction , in drug metabolism*Phase I Environmental Site Assessment, a report prepared for a real estate holding which identifies potential or existing environmental contamination liabilities*Phase 1 , a...
clinical trial in 2007 in various solid tumors. The Phase 1 trial is a multi-center, open-label, dose-escalation study in patients with solid tumor cancers. The primary objectives of the study are to determine the maximum tolerated dose (MTD) and dose-limiting toxicities of TH-302 in patients with advanced solid tumors and to establish the appropriate dose to be tested in Phase 2
PHASE 2
PHASE 2 is one of the most influential and well known New York City aerosol artist. Mostly active in the 1970s, Phase 2 is generally credited with originating the "bubble letter" style of aerosol writing, also known as "softies"...
clinical trials. The secondary objectives of the trial include establishing the pharmacokinetics
Pharmacokinetics
Pharmacokinetics, sometimes abbreviated as PK, is a branch of pharmacology dedicated to the determination of the fate of substances administered externally to a living organism...
and assessing the anti-tumor activity of TH-302, as measured by objective response rate and duration of response, and to characterize the safety profile. Tumors will be evaluated at baseline and every eight weeks using the Response Evaluation Criteria In Solid Tumors (RECIST) criteria.