CLADRIBINE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C10H12ClN5O3
Molecular Weight	285.687
Optical Activity	UNSPECIFIED
Defined Stereocenters	3 / 3
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

NC1=NC(Cl)=NC2=C1N=CN2[C@H]3C[C@H](O)[C@@H](CO)O3

InChI

InChIKey=PTOAARAWEBMLNO-KVQBGUIXSA-N

InChI=1S/C10H12ClN5O3/c11-10-14-8(12)7-9(15-10)16(3-13-7)6-1-4(18)5(2-17)19-6/h3-6,17-18H,1-2H2,(H2,12,14,15)/t4-,5+,6+/m0/s1

HIDE SMILES / InChI

Description
Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020229s034lbl.pdf
Curator's Comment: Description was created using several sources including: https://www.scripps.edu/newsandviews/e_20090601/MS.html; http://comtecmed.com/CONY/2008/Uploads/assets/speakers%20abstracts/stelmasiak.pdf

Cladribine is used for the treatment of hairy cell leukemia and multiple sclerosis (MS). As a purine analog, it is a synthetic anti-cancer agent that also suppresses the immune system. Chemically, it mimics the nucleoside adenosine and thus inhibits the enzyme adenosine deaminase, which interferes with the cell's ability to process DNA. It can be distinguished from other chemotherapeutic agents affecting purine metabolism in that it is cytotoxic to both actively dividing and quiescent lymphocytes and monocytes, inhibiting both DNA synthesis and repair. Cladribine injection is a potent antineoplastic agent with potentially significant toxic side effects. In MS, the novel mechanism of action of cladribine is expected to reduce inflammation, autoimmune effects and autoreactive cell damage, thereby improving the integrity of the blood–brain barrier. Thus, the effects of cladribine may target some of the key events that are central to the pathophysiology of MS.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
DNA polymerase beta 5 Target ID: P06746 Gene ID: 5423.0 Gene Symbol: POLB Target Organism: Homo sapiens (Human) Sources: http://www.ncbi.nlm.nih.gov/pubmed/?term=20634380	Inhibitor 8146
DNA 241 Target ID: CHEMBL2311221 Sources: http://www.ncbi.nlm.nih.gov/pubmed/?term=20634380	Binding Agent 1037
Adenosylhomocysteinase 5 Target ID: P23526 Gene ID: 191.0 Gene Symbol: AHCY Target Organism: Homo sapiens (Human) Sources: http://www.ncbi.nlm.nih.gov/pubmed/?term=20634380	Inhibitor 8146

Conditions

Condition	Modality	Targets	Highest Phase	Product
Hairy cell leukemia 2 Sources: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a2592a9b-bca6-4a5a-89c2-855a0634d5fe	Primary		Approved 8307	CLADRIBINE Approved Use the treatment of active Hairy Cell Leukemia as defined by clinically significant anemia, neutropenia, thrombocytopenia or disease-related symptoms. Launch Date 7.9185602E11

C_max

Value	Dose	Co-administered	Analyte	Population
20.57 ng/mL REVIEW https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/022561Orig1s000ClinPharmR.pdf	3 mg single, intravenous dose: 3 mg route of administration: Intravenous experiment type: SINGLE co-administered:		CLADRIBINE plasma	Homo sapiens population: UNHEALTHY age: UNKNOWN sex: UNKNOWN food status: UNKNOWN
29.05 ng/mL REVIEW https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/022561Orig1s000ClinPharmR.pdf	10 mg single, oral dose: 10 mg route of administration: Oral experiment type: SINGLE co-administered:		CLADRIBINE plasma	Homo sapiens population: UNHEALTHY age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
69.4 ng × h/mL REVIEW https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/022561Orig1s000ClinPharmR.pdf	3 mg single, intravenous dose: 3 mg route of administration: Intravenous experiment type: SINGLE co-administered:		CLADRIBINE plasma	Homo sapiens population: UNHEALTHY age: UNKNOWN sex: UNKNOWN food status: UNKNOWN
99.17 ng × h/mL REVIEW https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/022561Orig1s000ClinPharmR.pdf	10 mg single, oral dose: 10 mg route of administration: Oral experiment type: SINGLE co-administered:		CLADRIBINE plasma	Homo sapiens population: UNHEALTHY age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
18.4 h REVIEW https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/022561Orig1s000ClinPharmR.pdf	3 mg single, intravenous dose: 3 mg route of administration: Intravenous experiment type: SINGLE co-administered:		CLADRIBINE plasma	Homo sapiens population: UNHEALTHY age: UNKNOWN sex: UNKNOWN food status: UNKNOWN
19.7 h REVIEW https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/022561Orig1s000ClinPharmR.pdf	10 mg single, oral dose: 10 mg route of administration: Oral experiment type: SINGLE co-administered:		CLADRIBINE plasma	Homo sapiens population: UNHEALTHY age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
5.25 mg/kg multiple, oral (total) Highest studied dose Dose: 5.25 mg/kg Route: oral Route: multiple Dose: 5.25 mg/kg Sources: https://pubmed.ncbi.nlm.nih.gov/24502830 Page: p.262	unhealthy, ADULT n = 204 Health Status: unhealthy Condition: multiple sclerosis Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 204 Sources: https://pubmed.ncbi.nlm.nih.gov/24502830 Page: p.262	Disc. AE: Lymphopenia... AEs leading to discontinuation/dose reduction: Lymphopenia (grade 3-4) Sources: https://pubmed.ncbi.nlm.nih.gov/24502830 Page: p.262
8 mg/m2 1 times / day multiple, intravenous MTD Dose: 8 mg/m2, 1 times / day Route: intravenous Route: multiple Dose: 8 mg/m2, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/7911736 Page: p.170	unhealthy, ADULT n = 4 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 4 Sources: https://pubmed.ncbi.nlm.nih.gov/7911736 Page: p.170	DLT: Neutropenia, Leukopenia... Dose limiting toxicities: Neutropenia (grade 4, 50%) Leukopenia (grade 4, 50%) Sources: https://pubmed.ncbi.nlm.nih.gov/7911736 Page: p.170
0.07 mg/kg 1 times / day multiple, subcutaneous Studied dose Dose: 0.07 mg/kg, 1 times / day Route: subcutaneous Route: multiple Dose: 0.07 mg/kg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/10720289 Page: p.1152	unhealthy, ADULT n = 52 Health Status: unhealthy Condition: multiple sclerosis Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 52 Sources: https://pubmed.ncbi.nlm.nih.gov/10720289 Page: p.1152	Sources: https://pubmed.ncbi.nlm.nih.gov/10720289 Page: p.1152

AEs

AE	Significance	Dose	Population
Lymphopenia	grade 3-4 Disc. AE	5.25 mg/kg multiple, oral (total) Highest studied dose Dose: 5.25 mg/kg Route: oral Route: multiple Dose: 5.25 mg/kg Sources: https://pubmed.ncbi.nlm.nih.gov/24502830 Page: p.262	unhealthy, ADULT n = 204 Health Status: unhealthy Condition: multiple sclerosis Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 204 Sources: https://pubmed.ncbi.nlm.nih.gov/24502830 Page: p.262
Leukopenia	grade 4, 50% DLT	8 mg/m2 1 times / day multiple, intravenous MTD Dose: 8 mg/m2, 1 times / day Route: intravenous Route: multiple Dose: 8 mg/m2, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/7911736 Page: p.170	unhealthy, ADULT n = 4 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 4 Sources: https://pubmed.ncbi.nlm.nih.gov/7911736 Page: p.170
Neutropenia	grade 4, 50% DLT	8 mg/m2 1 times / day multiple, intravenous MTD Dose: 8 mg/m2, 1 times / day Route: intravenous Route: multiple Dose: 8 mg/m2, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/7911736 Page: p.170	unhealthy, ADULT n = 4 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 4 Sources: https://pubmed.ncbi.nlm.nih.gov/7911736 Page: p.170

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1670 inhibitor 1532 inducer 753	substrate 985 inhibitor 1695	substrate 1168 inhibitor 1789	inhibitor 1570

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 1463 CYP2B6 770 CYP2C8 869 CYP2C19 1410 CYP2E1 846 P-gp 1401 BCRP 678 MRP2 363 MRP4 202 MRP5 22 OATP1B1 770 OATP1B3 691 OAT1 584 OAT3 625 OAT4 145 OCT1 498 OCT2 630	CYP2E1 633 BCRP 545 P-gp 1491 MRP4 75 OCT2 336 OAT1 314 OAT3 328 OAT4 76 CYP1A2 1013 CYP2A6 510 CYP2C19 955	CYP1A2 671 CYP2B6 521

Drug as perpetrator

Target	Modality	Activity
BCRP 751	inhibitor 3185 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/	no
CYP1A2 1620	inducer 1515 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/	no
CYP1A2 1620	inhibitor 3185 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/ \| https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022561s000lbl.pdf	no
CYP2B6 946	inducer 1515 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/	no
CYP2B6 946	inhibitor 3185 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/ \| https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022561s000lbl.pdf	no
CYP2C19 1484	inhibitor 3185 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/ \| https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022561s000lbl.pdf	no
CYP2C8 923	inhibitor 3185 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/ \| https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022561s000lbl.pdf	no
CYP2C9 1747	inhibitor 3185 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/ \| https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022561s000lbl.pdf	no
CYP2D6 1826	inhibitor 3185 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/ \| https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022561s000lbl.pdf	no
CYP2E1 929	inhibitor 3185 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/ \| https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022561s000lbl.pdf	no
CYP3A4 1857	inducer 1515 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/	no
CYP3A4 1857	inhibitor 3185 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/ \| https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022561s000lbl.pdf	no
MRP2 452	inhibitor 3185 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/	no
MRP4 235	inhibitor 3185 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/	no
MRP5 47	inhibitor 3185 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/	no
OAT1 588	inhibitor 3185 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/	no
OAT3 627	inhibitor 3185 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/	no
OAT4 145	inhibitor 3185 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/	no
OATP1B1 785	inhibitor 3185 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/	no
OATP1B3 700	inhibitor 3185 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/	no
OCT1 513	inhibitor 3185 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/	no
OCT2 631	inhibitor 3185 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/	no
P-gp 1588	inhibitor 3185 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/	no

Drug as victim

Target	Modality	Activity
CYP1A2 1013	substrate 3264 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/	no
CYP2A6 510	substrate 3264 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/	no
CYP2C19 955	substrate 3264 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/	no
CYP2C9 985	substrate 3264 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/	no
CYP2D6 1168	substrate 3264 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/	no
CYP2E1 633	substrate 3264 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/	no
CYP3A4 1670	substrate 3264 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/	no
MRP4 75	substrate 3264 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/	no
OAT1 314	substrate 3264 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/	no
OAT3 328	substrate 3264 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/	no
OAT4 76	substrate 3264 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/	no
OCT2 336	substrate 3264 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/	no
BCRP 545	substrate 3264 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/ \| https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022561s000lbl.pdf \| https://pubmed.ncbi.nlm.nih.gov/18765824/	yes
P-gp 1491	substrate 3264 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/ \| https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022561s000lbl.pdf	yes

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1603	inhibitor 1584 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:567361	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:567361
MolPort	MolPort-002-054-532	https://www.molport.com/shop/molecule-link/MolPort-002-054-532
Selleck Chemicals	Cladribine	http://www.selleckchem.com/products/Cladribine.html
ZINC	ZINC000003798064	http://zinc15.docking.org/substances/ZINC000003798064
eMolecules	29542740	https://www.emolecules.com/cgi-bin/more?vid=29542740

PubMed

Title	Date	PubMed
Expression and release of chemokines associated with apoptotic cell death in human promonocytic U937 cells and peripheral blood mononuclear cells.	1999 Oct	10540334
Guillain-Barre syndrome following 2-chlorodeoxyadenosine treatment for Hairy Cell Leukemia.	2000 Nov	11342351
Flow cytometry of peripheral blood and bone marrow cells from patients with hairy cell leukemia: phenotype of hairy cells, lymphocyte subsets and detection of minimal residual disease after treatment.	2001	11845978
Richter's syndrome following cladribine therapy for chronic lymphocytic leukemia first manifested as pathologic fracture of the femur.	2001 Aug	11697509
Effect of cladribine treatment on beta-2 microglobulin and soluble intercellular adhesion molecule 1 (ICAM-1) in patients with multiple sclerosis.	2001 Aug	11552664
Cladribine. Ortho Biotech Inc.	2001 Dec	11892941
2-chlorodeoxyadenosine (cladribine) in the treatment of hairy cell leukemia.	2001 Jan	11310372
Unexpectedly high incidence of hypoplastic/aplastic foci in bone marrow biopsies of hairy cell leukemia patients in remission following 2-chlorodeoxyadenosine therapy.	2001 Jan	11168501
Gynecomastia in a case of hairy cell leukaemia--cladribine induced?	2001 Jun	11699216
Nucleoside analogues: mechanisms of drug resistance and reversal strategies.	2001 Jun	11417472
Human cytosolic 5'-nucleotidase I: characterization and role in nucleoside analog resistance.	2001 Mar 30	11133996
Immunologic therapy for secondary and primary progressive multiple sclerosis.	2001 May	11898531
Therapeutic advances in the treatment of hairy cell leukemia.	2001 May	11301103
Novel treatment strategies in chronic lymphocytic leukemia.	2001 May	11296131
Prolymphocytic leukemia or prolymphocytic transformation of mantle cell lymphoma.	2001 Nov	11710698
Resistance to 2-chloro-2'-deoxyadenosine of the human B-cell leukemia cell line EHEB.	2001 Nov	11705877
Acquisition of human concentrative nucleoside transporter 2 (hcnt2) activity by gene transfer confers sensitivity to fluoropyrimidine nucleosides in drug-resistant leukemia cells.	2001 Nov	11641443
Efficacy of anti-CD20 monoclonal antibodies (Mabthera) in patients with progressed hairy cell leukemia.	2001 Oct	11602410
Gateways to Clinical Trials.	2002 Apr	12087878
The role of mitoxantrone in non-Hodgkin's lymphoma.	2002 Apr	12017536
Simultaneous diagnosis of hairy cell leukemia and chronic lymphocytic leukemia/small lymphocytic lymphoma: a frequent association?	2002 Aug	12145685
Induction of apoptosis by cladribine (2-CdA), gemcitabine and other chemotherapeutic drugs on CD34+/CD38+ and CD34+/CD38- hematopoietic progenitor cells: selective effects of doxorubicin and 2-CdA with protection of immature cells.	2002 Feb	11999573
Radiation therapy and combination of cladribine, cyclophosphamide, and prednisone as treatment of Bing-Neel syndrome: Case report and review of the literature.	2002 Feb	11835349
2-Chloro-2'-deoxyadenosine inhibits DNA repair synthesis and potentiates UVC cytotoxicity in chronic lymphocytic leukemia B lymphocytes.	2002 Jan	11840261
Cladribine (2-chlorodeoxyadenosine) therapy in hairy cell leukemia variant. A report of three cases.	2002 Jan	11801472
Anti-CD20 antibody (IDEC-C2B8, rituximab) enhances efficacy of cytotoxic drugs on neoplastic lymphocytes in vitro: role of cytokines, complement, and caspases.	2002 Jan	11801463
Cytotoxicity of 2-chlorodeoxyadenosine and arabinosylcytosine in leukaemic lymphoblasts from paediatric patients: significance of cellular nucleoside transporter content.	2002 Mar	11849208

Patents

Sample Use Guides

In Vivo Use Guide

0.09 mg/kg/day

Route of Administration: Intravenous

In Vitro Use Guide

0.05 - 0.4 uM

Name

Type

Language

CLADRIBINE

Official Name

English

CLADRIBINE [HSDB]

Common Name

English

CLADRIBINE [EP MONOGRAPH]

Common Name

English

MAVENCLAD

Common Name

English

2-CHLORODEOXYADENOSINE

Systematic Name

English

2-CDA

Common Name

English

CLADRIBINE [USP MONOGRAPH]

Common Name

English

CLADRIBINE [USP-RS]

Common Name

English

LITAK

Brand Name

English

cladribine [INN]

Common Name

English

CLADRIBINE [MART.]

Common Name

English

Cladribine [WHO-DD]

Common Name

English

ADENOSINE, 2-CHLORO-2'-DEOXY-

Systematic Name

English

2-CHLORO-2'-DEOXYADENOSINE

Systematic Name

English

CLADRIBINE [ORANGE BOOK]

Common Name

English

NSC-105014

Code

English

CLADRIBINE [EMA EPAR]

Common Name

English

LEUSTATIN

Brand Name

English

CLADRIBINE [MI]

Common Name

English

CLADRIBINE [VANDF]

Common Name

English

CLADRIBINE [JAN]

Common Name

English

RWJ-26251

Code

English

CLADRIBINE [USP IMPURITY]

Common Name

English

CLADRIBINE [USAN]

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C2157