Obatoclax: Difference between revisions

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{{chembox
{{Chembox
| ImageFile = Obatoclax.svg
| ImageFile   = Obatoclax.svg
| ImageSize = 200px
| ImageSize   = 200px
| IUPACName = 2-(2-((3,5-Dimethyl-1''H''-pyrrol-2-yl)methylene)-3-methoxy-2''H''-pyrrol-5-yl)-1''H''-indole
| IUPACName   = 2-(2-((3,5-Dimethyl-1''H''-pyrrol-2-yl)methylene)-3-methoxy-2''H''-pyrrol-5-yl)-1''H''-indole
| OtherNames = GX15-070
| OtherNames = GX15-070
|Section1={{Chembox Identifiers
 
| UNII_Ref = {{fdacite|correct|FDA}}
| Section1 = {{Chembox Identifiers
| UNII = QN4128B52A
| UNII_Ref     = {{fdacite|correct|FDA}}
| CASNo = 803712-67-6
| UNII         = QN4128B52A
| CASNo_Ref = {{cascite|correct|CAS}}
| CASNo         = 803712-67-6
| CASNo1 = 803712-79-0
| CASNo_Ref     = {{cascite|correct|CAS}}
| CASNo1       = 803712-79-0
| CASNo1_Comment = ([[mesylate]])
| CASNo1_Comment = ([[mesylate]])
| CASNo1_Ref = {{cascite|correct|CAS}}
| CASNo1_Ref   = {{cascite|correct|CAS}}
| PubChem = 11404337
| PubChem       = 11404337
| PubChem1 = 16681698
| PubChem1     = 16681698
| PubChem1_Comment = ([[mesylate]])
| PubChem1_Comment = ([[mesylate]])
| ChemSpiderID = 24539359
| ChemSpiderID = 24539359
| SMILES = Cc1cc([nH]c1/C=C/2\C(=CC(=N2)c3cc4ccccc4[nH]3)OC)C
| SMILES       = Cc1cc([nH]c1/C=C/2\C(=CC(=N2)c3cc4ccccc4[nH]3)OC)C
| InChI =1S/C20H19N3O/c1-12-8-13(2)21-16(12)10-19-20(24-3)11-18(23-19)17-9-14-6-4-5-7-15(14)22-17/h4-11,21-22H,1-3H3/b19-10+
| InChI         = 1S/C20H19N3O/c1-12-8-13(2)21-16(12)10-19-20(24-3)11-18(23-19)17-9-14-6-4-5-7-15(14)22-17/h4-11,21-22H,1-3H3/b19-10+
  }}
}}
|Section2={{Chembox Properties
 
| C=20 | H=19 | N=3 | O=1  
| Section2 = {{Chembox Properties
| Appearance =  
| C = 20 | H = 19 | N = 3 | O = 1
| Density =  
| Appearance   = Not available
| MeltingPt =  
| Density     = Not available
| BoilingPt =  
| MeltingPt   = Not available
| Solubility =
| BoilingPt   = Not available
  }}
| Solubility  = Not available
|Section3={{Chembox Hazards
| MainHazards =
| FlashPt =
| AutoignitionPt =
   }}
|Section5={{Chembox Pharmacology
| AdminRoutes =
| Bioavail =
| Metabolism =
| HalfLife =
| ProteinBound =
| Excretion =
| Legal_status =
| Legal_US =
| Legal_UK =
| Legal_AU =
| Legal_CA =
| PregCat =
| PregCat_AU =
| PregCat_US = }}
}}
}}


'''Obatoclax mesylate''', also known as GX15-070, is an experimental drug for the treatment of various types of cancer.  It was discovered by Gemin X, which was acquired by [[Cephalon]], which has since been acquired by [[Teva Pharmaceuticals]].<ref>[http://www.prnewswire.com/news-releases/cephalon-announces-definitive-agreement-to-acquire-gemin-x-118386434.html Cephalon Announces Definitive Agreement to Acquire Gemin X], March 21, 2011</ref>  Several [[Phase II clinical trials]] were completed that investigated use of Obatoclax in the treatment of [[leukemia]], [[lymphoma]], [[myelofibrosis]], and [[mastocytosis]].<ref>{{cite journal |doi=10.3816/CLML.2010.n.059 |pmid=20709666 |title=Phase II Study of Obatoclax Mesylate (GX15-070), a Small-Molecule BCL-2 Family Antagonist, for Patients with Myelofibrosis |journal=Clinical Lymphoma, Myeloma & Leukemia |volume=10 |issue=4 |pages=285–9 |year=2010 |last1=Parikh |first1=Sameer A. |last2=Kantarjian |first2=Hagop |last3=Schimmer |first3=Aaron |last4=Walsh |first4=William |last5=Asatiani |first5=Ekatherine |last6=El-Shami |first6=Khaled |last7=Winton |first7=Elliott |last8=Verstovsek |first8=Srdan }}</ref><ref>[https://www.drugs.com/clinical_trials/gemin-x-presents-new-data-obatoclax-american-society-hematology-meeting-6469.html Gemin X Presents New Data on Obatoclax at the American Society of Hematology Meeting], Dec 9, 2008</ref><ref>[http://clinicaltrials.gov/search/intervention=Obatoclax Obatoclax] at [[ClinicalTrials.gov]]</ref>
| Section3 = {{Chembox Hazards
| MainHazards    = Investigational use only
| FlashPt        = Not applicable
| AutoignitionPt  = Not applicable
}}


==Mechanism of action==
| Section5 = {{Chembox Pharmacology
| AdminRoutes    = Intravenous
| Bioavail        = Not well established
| Metabolism      = Hepatic (cytochrome P450 involvement suspected)
| HalfLife        = Short; varies by individual and dosage
| ProteinBound    = Not fully determined
| Excretion      = Likely hepatic/renal pathways
| Legal_status    = Investigational
| Legal_US        = Investigational New Drug
| Legal_UK        = Unlicensed
| Legal_AU        = Not approved
| Legal_CA        = Not approved
| PregCat        = Not assigned
| PregCat_AU      = Not available
| PregCat_US      = Not assigned
}}
}}


Obatoclax is an [[enzyme inhibitor|inhibitor]] of the [[Bcl-2 family]] of [[protein]]s.<ref>{{cite journal |doi=10.1158/0008-5472.CAN-07-1919 |pmid=18451169 |pmc=4096127 |title=Mechanisms of Antileukemic Activity of the Novel Bcl-2 Homology Domain-3 Mimetic GX15-070 (Obatoclax) |journal=Cancer Research |volume=68 |issue=9 |pages=3413–20 |year=2008 |last1=Konopleva |first1=M. |last2=Watt |first2=J. |last3=Contractor |first3=R. |last4=Tsao |first4=T. |last5=Harris |first5=D. |last6=Estrov |first6=Z. |last7=Bornmann |first7=W. |last8=Kantarjian |first8=H. |last9=Viallet |first9=J. |last10=Samudio |first10=I. |last11=Andreeff |first11=M. }}</ref>  This inhibition induces [[apoptosis]] in cancer cells, preventing tumor growth. Solubility has been an issue in the development of the drug.<ref>{{cite journal |doi=10.1186/s12885-015-1582-5 |title=Obatoclax is a direct and potent antagonist of membrane-restricted Mcl-1 and is synthetic lethal with treatment that induces Bim |journal=BMC Cancer |volume=15 |year=2015 |last1=Nguyen |first1=Mai |last2=Cencic |first2=Regina |last3=Ertel |first3=Franziska |last4=Bernier |first4=Cynthia |last5=Pelletier |first5=Jerry |last6=Roulston |first6=Anne |last7=Silvius |first7=John R. |last8=Shore |first8=Gordon C. |pmc=4522062 }}</ref>
'''Obatoclax mesylate''', also known as '''GX15-070''', is an experimental small molecule drug designed to promote [[apoptosis]] (programmed cell death) in cancer cells by acting as a [[Bcl-2 family]] protein antagonist. It was developed by Gemin X Biotechnologies and later acquired by [[Cephalon]], which itself was acquired by [[Teva Pharmaceutical Industries]].


== Clinical trials ==
==Mechanism of Action==
Clinical trial results have been published for treatment of [[acute myeloid leukemia]],<ref>{{cite journal |doi=10.1371/journal.pone.0108694 |pmid=25285531 |pmc=4186779 |title=A Multicenter Phase I/II Study of Obatoclax Mesylate Administered as a 3- or 24-Hour Infusion in Older Patients with Previously Untreated Acute Myeloid Leukemia |journal=PLoS ONE |volume=9 |issue=10 |pages=e108694 |year=2014 |last1=Schimmer |first1=Aaron D. |last2=Raza |first2=Azra |last3=Carter |first3=Thomas H. |last4=Claxton |first4=David |last5=Erba |first5=Harry |last6=Deangelo |first6=Daniel J. |last7=Tallman |first7=Martin S. |last8=Goard |first8=Carolyn |last9=Borthakur |first9=Gautam |bibcode=2014PLoSO...9j8694S }}</ref> small cell lung cancer,<ref>{{cite journal |doi=10.1016/j.lungcan.2014.05.003 |pmid=24997137 |title=Randomized phase II study of carboplatin and etoposide with or without obatoclax mesylate in extensive-stage small cell lung cancer |journal=Lung Cancer |volume=85 |issue=3 |pages=420–8 |year=2014 |last1=Langer |first1=Corey J. |last2=Albert |first2=Istvan |last3=Ross |first3=Helen J. |last4=Kovacs |first4=Peter |last5=Blakely |first5=L. Johnetta |last6=Pajkos |first6=Gabor |last7=Somfay |first7=Attila |last8=Zatloukal |first8=Petr |last9=Kazarnowicz |first9=Andrzej |last10=Moezi |first10=Mehdi M. |last11=Schreeder |first11=Marshall T. |last12=Schnyder |first12=Judy |last13=Ao-Baslock |first13=Ada |last14=Pathak |first14=Ashutosh K. |last15=Berger |first15=Mark S. }}</ref> [[Hodgkin's lymphoma]],<ref>{{cite journal |doi=10.1182/blood-2011-11-391037 |pmid=22383790 |title=Experience with obatoclax mesylate (GX15-070), a small molecule pan-Bcl-2 family antagonist in patients with relapsed or refractory classical Hodgkin lymphoma |journal=Blood |volume=119 |issue=9 |pages=2171–2 |year=2012 |last1=Oki |first1=Y. |last2=Copeland |first2=A. |last3=Hagemeister |first3=F. |last4=Fayad |first4=L. E. |last5=Fanale |first5=M. |last6=Romaguera |first6=J. |last7=Younes |first7=A. }}</ref> myelodysplastic syndromes,<ref>{{cite journal |doi=10.1016/j.clml.2014.04.007 |pmid=25052051 |title=A Phase II, Multicenter, Open-Label Study of Obatoclax Mesylate in Patients with Previously Untreated Myelodysplastic Syndromes with Anemia or Thrombocytopenia |journal=Clinical Lymphoma, Myeloma & Leukemia |volume=14 |issue=6 |pages=534–9 |year=2014 |last1=Arellano |first1=Martha L. |last2=Borthakur |first2=Gautam |last3=Berger |first3=Mark |last4=Luer |first4=Jill |last5=Raza |first5=Azra }}</ref>
Obatoclax is a pan-inhibitor of the anti-apoptotic [[Bcl-2 protein family]], which includes [[Bcl-2]], [[Bcl-xL]], and [[Mcl-1]]. These proteins help cancer cells evade apoptosis. By binding to these proteins, obatoclax restores apoptotic pathways in cancerous cells, potentially enabling effective treatment of [[hematologic malignancies]] and [[solid tumors]].


Teva halted a phase III trial in patients with lung cancer before it had begun, citing "business decisions" as the reason.<ref>{{ClinicalTrialsGov|NCT01563601|Efficacy and Safety of Obatoclax Mesylate in Combination With Carboplatin and Etoposide Compared With Carboplatin and Etoposide Alone in Chemotherapy-Naive Patients With Extensive-Stage Small Cell Lung Cancer}}</ref>
==Clinical Development==
Obatoclax mesylate has been evaluated in multiple [[phase I]] and [[phase II]] [[clinical trials]] for cancers such as:
* [[Chronic lymphocytic leukemia]] (CLL)
* [[Small-cell lung cancer]] (SCLC)
* [[Acute myeloid leukemia]] (AML)
* [[Multiple myeloma]]
* [[Hodgkin lymphoma]]
* [[Melanoma]]


== See also ==
Despite promising preclinical results, clinical outcomes have been limited due to [[toxicity]], particularly [[neurotoxicity]], and modest therapeutic efficacy. Research is ongoing to understand its full potential in combination therapies.
* [[Navitoclax]]


==References==
==Side Effects==
{{reflist}}
The most commonly reported adverse effects include:
* [[Neurological symptoms]] such as euphoria, hallucinations, and somnolence
* [[Gastrointestinal issues]] (nausea, vomiting)
* Fatigue
* Transient hypotension
 
==Status==
As of now, obatoclax is an investigational agent and has not been approved for general clinical use in any country. It continues to be explored in research settings, especially in combination with other chemotherapeutic or targeted agents.
 
==See also==
* [[Bcl-2 inhibitor]]
* [[Apoptosis]]
* [[Targeted therapy]]
* [[Investigational drug]]
 
==External links==
* [https://pubchem.ncbi.nlm.nih.gov/compound/11404337 PubChem Entry for Obatoclax]
* [https://clinicaltrials.gov/ct2/results?cond=&term=obatoclax ClinicalTrials.gov: Obatoclax Trials]


[[Category:Experimental cancer drugs]]
[[Category:Experimental cancer drugs]]
[[Category:Bcl-2 inhibitors]]
[[Category:Antineoplastic drugs]]
[[Category:Indoles]]
[[Category:Indoles]]
[[Category:Pyrroles]]
[[Category:Pyrroles]]
 
[[Category:Teva Pharmaceuticals brands]]
 
{{antineoplastic-drug-stub}}

Revision as of 23:25, 2 April 2025

Chemical Compound
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GHS Pictograms [[File:|50px]]
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References

Obatoclax mesylate, also known as GX15-070, is an experimental small molecule drug designed to promote apoptosis (programmed cell death) in cancer cells by acting as a Bcl-2 family protein antagonist. It was developed by Gemin X Biotechnologies and later acquired by Cephalon, which itself was acquired by Teva Pharmaceutical Industries.

Mechanism of Action

Obatoclax is a pan-inhibitor of the anti-apoptotic Bcl-2 protein family, which includes Bcl-2, Bcl-xL, and Mcl-1. These proteins help cancer cells evade apoptosis. By binding to these proteins, obatoclax restores apoptotic pathways in cancerous cells, potentially enabling effective treatment of hematologic malignancies and solid tumors.

Clinical Development

Obatoclax mesylate has been evaluated in multiple phase I and phase II clinical trials for cancers such as:

Despite promising preclinical results, clinical outcomes have been limited due to toxicity, particularly neurotoxicity, and modest therapeutic efficacy. Research is ongoing to understand its full potential in combination therapies.

Side Effects

The most commonly reported adverse effects include:

Status

As of now, obatoclax is an investigational agent and has not been approved for general clinical use in any country. It continues to be explored in research settings, especially in combination with other chemotherapeutic or targeted agents.

See also

External links

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