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 8297
DNA 278 Target ID: CHEMBL2311221 Sources: http://www.ncbi.nlm.nih.gov/pubmed/?term=20634380	Binding Agent 1064
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 8297

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 8429	CLADRIBINE Approved Use the treatment of active Hairy Cell Leukemia as defined by clinically significant anemia, neutropenia, thrombocytopenia or disease-related symptoms. Launch Date 1995

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 1737 inhibitor 1587 inducer 781	substrate 1037 inhibitor 1767	substrate 1217 inhibitor 1852	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 1524 CYP2B6 810 CYP2C8 911 CYP2C19 1478 CYP2E1 882 P-gp 1461 BCRP 699 MRP2 383 MRP4 204 MRP5 22 OATP1B1 788 OATP1B3 706 OAT1 599 OAT3 642 OAT4 146 OCT1 512 OCT2 647	CYP2E1 667 BCRP 561 P-gp 1537 MRP4 77 OCT2 355 OAT1 326 OAT3 339 OAT4 78 CYP1A2 1054 CYP2A6 543 CYP2C19 991	CYP1A2 701 CYP2B6 547

Drug as perpetrator

Target	Modality	Activity
BCRP 773	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/	no
CYP1A2 1692	inducer 1573 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/	no
CYP1A2 1692	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/ \| https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022561s000lbl.pdf	no
CYP2B6 1001	inducer 1573 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/	no
CYP2B6 1001	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/ \| https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022561s000lbl.pdf	no
CYP2C19 1553	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/ \| https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022561s000lbl.pdf	no
CYP2C8 965	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/ \| https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022561s000lbl.pdf	no
CYP2C9 1819	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/ \| https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022561s000lbl.pdf	no
CYP2D6 1891	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/ \| https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022561s000lbl.pdf	no
CYP2E1 970	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/ \| https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022561s000lbl.pdf	no
CYP3A4 1925	inducer 1573 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/	no
CYP3A4 1925	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/ \| https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022561s000lbl.pdf	no
MRP2 475	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/	no
MRP4 238	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/	no
MRP5 48	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/	no
OAT1 603	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/	no
OAT3 644	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/	no
OAT4 146	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/	no
OATP1B1 803	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/	no
OATP1B3 715	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/	no
OCT1 543	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/	no
OCT2 648	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/	no
P-gp 1650	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/	no

Drug as victim

Target	Modality	Activity
CYP1A2 1054	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/	no
CYP2A6 543	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/	no
CYP2C19 991	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/	no
CYP2C9 1037	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/	no
CYP2D6 1217	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/	no
CYP2E1 667	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/	no
CYP3A4 1737	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/	no
MRP4 77	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/	no
OAT1 326	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/	no
OAT3 339	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/	no
OAT4 78	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/	no
OCT2 355	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/29987837/	no
BCRP 561	substrate 3367 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 1537	substrate 3367 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 1647	inhibitor 1626 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
Cladribine combined with mitoxantrone in the treatment of blastic phase of chronic myeloid leukemia.	2001	11583290
2-chlorodeoxyadenosine (cladribine) in the treatment of hairy cell leukemia.	2001 Jan	11310372
Treatment options in Waldenström's macroglobulinaemia: the role of the purine analogues.	2001 Jun	11585010
Nucleoside analogues in the treatment of haematological malignancies.	2001 Jun	11585009
Systematic review of immunomodulatory drugs for the treatment of people with multiple sclerosis: Is there good quality evidence on effectiveness and cost?	2001 May	11309449
The role of mitoxantrone in non-Hodgkin's lymphoma.	2002 Apr	12017536
Therapeutic potential of a reduced-intensity preparative regimen for allogeneic transplantation with cladribine, busulfan, and antithymocyte globulin against advanced/refractory acute leukemia/lymphoma.	2002 Apr	11948108
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
Bax expression correlates with cellular drug sensitivity to doxorubicin, cyclophosphamide and chlorambucil but not fludarabine, cladribine or corticosteroids in B cell chronic lymphocytic leukemia.	2002 Jun	12040435
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