CLOFARABINE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C10H11ClFN5O3
Molecular Weight	303.677
Optical Activity	UNSPECIFIED
Defined Stereocenters	4 / 4
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

NC1=NC(Cl)=NC2=C1N=CN2[C@@H]3O[C@H](CO)[C@@H](O)[C@@H]3F

InChI

InChIKey=WDDPHFBMKLOVOX-AYQXTPAHSA-N

InChI=1S/C10H11ClFN5O3/c11-10-15-7(13)5-8(16-10)17(2-14-5)9-4(12)6(19)3(1-18)20-9/h2-4,6,9,18-19H,1H2,(H2,13,15,16)/t3-,4+,6-,9-/m1/s1

HIDE SMILES / InChI

Molecular Formula	C10H11ClFN5O3
Molecular Weight	303.677
Charge	0
Count

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	4 / 4
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/22840768
Curator's Comment: description was created based on several sources, including http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021673s024lbl.pdf

Clofarabine is a anti-cancer drug which was approved by FDA for the treatment of pediatric patients with relapsed or refractory acute lymphoblastic leukemia. After crossing the cell membrane the drug is rapidly metabolized by deoxycytidine kinase to diphosphate and triphosphate metabolites and these metabolites reversibly inhibit hRNR by binding to alpha subunit. Also the triphosphate is incorporated to DNA where it acts as a chain terminator.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
DNA 247 Target ID: CHEMBL2311221 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021673s024lbl.pdf	Binding Agent 1059
Ribonucleoside-diphosphate reductase RR1 14 Target ID: CHEMBL2095215 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021673s024lbl.pdf	Inhibitor 8228		17.0 nM [Ki]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Relapsed or refractory acute lymphoblastic leukemia 2 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021673s024lbl.pdf	Primary		Approved 8360	CLOLAR Approved Use Clolar® (clofarabine) Injection is indicated for the treatment of pediatric patients 1 to 21 years old with relapsed or refractory acute lymphoblastic leukemia after at least two prior regimens. Launch Date 1.10419195E12

C_max

Value	Dose	Co-administered	Analyte	Population
308 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/28509593	40 mg/m² 1 times / day multiple, intravenous dose: 40 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered: CYTARABINE	CYTARABINE	CLOFARABINE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
1793 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/28509593	40 mg/m² 1 times / day multiple, intravenous dose: 40 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered: CYTARABINE	CYTARABINE	CLOFARABINE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
28 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/29773602	40 mg/m² 1 times / day multiple, intravenous dose: 40 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:		CLOFARABINE blood	Homo sapiens population: UNHEALTHY age: CHILD sex: UNKNOWN food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
4.9 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/28509593	40 mg/m² 1 times / day multiple, intravenous dose: 40 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered: CYTARABINE	CYTARABINE	CLOFARABINE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
1.5 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/29773602	40 mg/m² 1 times / day multiple, intravenous dose: 40 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:		CLOFARABINE blood	Homo sapiens population: UNHEALTHY age: CHILD sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
55 mg/m2 1 times / day multiple, intravenous Highest studied dose Dose: 55 mg/m2, 1 times / day Route: intravenous Route: multiple Dose: 55 mg/m2, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/12637486	unhealthy, 42 years n = 4 Health Status: unhealthy Condition: acute leukemia Age Group: 42 years Sex: M+F Population Size: 4 Sources: https://pubmed.ncbi.nlm.nih.gov/12637486	Other AEs: Nausea, Diarrhea... Other AEs: Nausea (grade 1-2, 2 patients) Diarrhea (grade 1, 3 patients) Hepatotoxicity (grade 3, 2 patients) Sources: https://pubmed.ncbi.nlm.nih.gov/12637486
40 mg/m2 1 times / day multiple, intravenous MTD Dose: 40 mg/m2, 1 times / day Route: intravenous Route: multiple Dose: 40 mg/m2, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/12637486	unhealthy, 42 years n = 31 Health Status: unhealthy Condition: acute leukemia Age Group: 42 years Sex: M+F Population Size: 31 Sources: https://pubmed.ncbi.nlm.nih.gov/12637486	Other AEs: Nausea, Fatigue... Other AEs: Nausea (grade 1-2, 3 patients) Fatigue (grade 3, 1 patient) Diarrhea (grade 1, 2 patients) Cramp (grade 1, 1 patient) Anorexia (grade 1, 1 patient) Mucositis (grade 1, 1 patient) Edema (grade 1, 1 patient) Hepatotoxicity (grade 3-4, 4 patients) Sources: https://pubmed.ncbi.nlm.nih.gov/12637486
2 mg/m2 1 times / day multiple, intravenous MTD Dose: 2 mg/m2, 1 times / day Route: intravenous Route: multiple Dose: 2 mg/m2, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/12637486	unhealthy, 51 years n = 6 Health Status: unhealthy Condition: solid tumors Age Group: 51 years Sex: M+F Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/12637486	DLT: Myelosuppression... Dose limiting toxicities: Myelosuppression (grade 3, 2 patients) Sources: https://pubmed.ncbi.nlm.nih.gov/12637486
6 mg 1 times / day multiple, oral Highest studied dose Dose: 6 mg, 1 times / day Route: oral Route: multiple Dose: 6 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/24415560	unhealthy, 60-76 years n = 1 Health Status: unhealthy Condition: Acute Myeloid Leukemia Age Group: 60-76 years Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/24415560	Other AEs: Nausea, Hypoalbuminemia... Other AEs: Nausea (grade 1-2, 1 patient) Hypoalbuminemia (grade 1-2, 1 patient) Blood bilirubin decreased (grade 1-2, 1 patient) Lymphopenia (grade 3-4) Sources: https://pubmed.ncbi.nlm.nih.gov/24415560
70 mg/m2 1 times / day multiple, intravenous Highest studied dose Dose: 70 mg/m2, 1 times / day Route: intravenous Route: multiple Dose: 70 mg/m2, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2004/021673lbl.pdf	unhealthy, child n = 2 Health Status: unhealthy Condition: ALL Age Group: child Population Size: 2 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2004/021673lbl.pdf	Other AEs: Hyperbilirubinemia, Vomiting... Other AEs: Hyperbilirubinemia (grade 4, 2 patients) Vomiting (grade 2-3, 2 patients) Maculopapular rash (grade 3, 2 patients) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2004/021673lbl.pdf

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
			inhibitor 1599

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
	CYP450 65

Drug as victim

Target	Modality	Activity	Metabolite	Clinical evidence
CYP450 65	substrate 3326 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-673_Clolar_biopharmr.PDF#page=18 Page: 18.0	no

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1632	inhibitor 1613 Sources: https://www.pharmadoor.com.br/images/medicamentos/bulas/clolar_bula.pdf#page=30 Page: 30.0

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:681569	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:681569
MolPort	MolPort-005-941-711	https://www.molport.com/shop/molecule-link/MolPort-005-941-711
Selleck Chemicals	Clofarabine	http://www.selleckchem.com/products/Clofarabine.html
ZINC	ZINC000003798247	http://zinc15.docking.org/substances/ZINC000003798247
eMolecules	29256989	https://www.emolecules.com/cgi-bin/more?vid=29256989
eMolecules	30512527	https://www.emolecules.com/cgi-bin/more?vid=30512527

PubMed

Title	Date	PubMed
Nucleoside analogues in the treatment of haematological malignancies.	2001 Jun	11585009
Gateways to Clinical Trials.	2002 Apr	12087878
New drugs in acute myeloid leukemia.	2002 Sep	12162909
Clofarabine-induced acral erythema during the treatment of patients with myelodysplasia and acute leukemia: report of two cases.	2003 Aug	12952235
Advanced-phase chronic myeloid leukemia.	2003 Jan	12563614
Gateways to clinical trials.	2003 Jul-Aug	12949633
Comparison of cytotoxicity of 2-chloro- 2'-arabino-fluoro-2'-deoxyadenosine (clofarabine) with cladribine in mononuclear cells from patients with acute myeloid and chronic lymphocytic leukemia.	2003 Mar	12651272
Phase I clinical and pharmacology study of clofarabine in patients with solid and hematologic cancers.	2003 Mar 15	12637486
Gateways to clinical trials.	2003 Nov	14685303
Gateways to clinical trials.	2004 Jan-Feb	14988742
Gateways to clinical trials.	2004 Jul-Aug	15349141
Nucleosides as anticancer agents: from concept to the clinic.	2005	17150610
Biochemical modulation of cytarabine triphosphate by clofarabine.	2005 Apr	15723262
Plasma and cerebrospinal fluid pharmacokinetics of clofarabine in nonhuman primates.	2005 Aug 15	16115942
The distribution, metabolism, and elimination of clofarabine in rats.	2005 Jun	15743978
Purine nucleoside analogs as immunosuppressive and antineoplastic agents: mechanism of action and clinical activity.	2006	17168705
Phase II study of clofarabine in pediatric patients with refractory or relapsed acute lymphoblastic leukemia.	2006 Apr 20	16622268
Clinical and pharmacokinetic study of clofarabine in chronic lymphocytic leukemia: strategy for treatment.	2006 Jul 1	16818700
Pharmacological and clinical studies on purine nucleoside analogs--new anticancer agents.	2006 May	16719832
The activity and toxicity of low dose clofarabine against relapsed or refractory myeloma.	2006 Nov	17043015
Clofarabine and nelarabine: two new purine nucleoside analogs.	2006 Nov	16988579
Gateways to clinical trials.	2006 Oct	17136234
A tale of two drugs.	2006 Oct	17078168
Discovery and development of clofarabine: a nucleoside analogue for treating cancer.	2006 Oct	17016426
Advances in the management of AML in the elderly.	2007 Mar	17519879
Acute myeloid leukemia in the elderly: conventional and novel treatment approaches.	2008 Jul	18433953
Potential role of novel nucleoside analogs in the treatment of acute myeloid leukemia.	2008 Mar	18300755
Polyadenylation inhibition by the triphosphates of deoxyadenosine analogues.	2008 Oct	18433867

Patents

Sample Use Guides

In Vivo Use Guide

The recommended pediatric dose is 52 mg/m2 given as an intravenous infusion over 2 hours daily for 5 consecutive days of a 28-day cycle. Repeat cycles every 2-6 week.

Route of Administration: Intravenous

In Vitro Use Guide

HL-60 cells or HL/ara-C20 cells were incubated with different concentrations of clofarabine for 72 h. The 50%-growth-inhibitory concentration IC50 was 50 nM for HL60 and 320 nM for HL/ara-C20 cells.

Substance Class	Chemical Created by `admin` on `Wed Jul 05 23:04:05 UTC 2023` Edited by `admin` on `Wed Jul 05 23:04:05 UTC 2023`
Record UNII	762RDY0Y2H
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

CLOFARABINE

Official Name

English

CLOFARABINE [VANDF]

Common Name

English

CLOFARABINE [MI]

Common Name

English

9H-PURIN-6-AMINE, 2-CHLORO-9-(2-DEOXY-2-FLUORO-.BETA.-D-ARABINOFURANOSYL)

Common Name

English

CLOLAR

Brand Name

English

clofarabine [INN]

Common Name

English

CLOFARABINE [ORANGE BOOK]

Common Name

English

Clofarabine [WHO-DD]

Common Name

English

NSC-759857

Code

English

CLOFARABINE [EMA EPAR]

Common Name

English

CLOFARABINE [USAN]

Common Name

English

CLOFARABINE [MART.]

Common Name

English

EVOLTRA

Brand Name

English

CLOFARABINE [JAN]

Common Name

English

2-CHLORO-9-(2-DEOXY-2-FLUORO-.BETA.-D-ARABINOFURANOSYL)-9H-PURIN-6-AMINE

Common Name

English

Classification Tree Code System Code

FDA ORPHAN DRUG

668118