Drug Information

Drug (ID: DG00134) and It's Reported Resistant Information

• Name: Mercaptopurine
• Synonyms: 6-mercaptopurine; Ismipur; Leukerin; Leupurin; Mercaleukim; Mercaleukin; Mercaptopurin; Mercaptopurina; Mercaptopurinum; Mercapurin; Merkaptopuryna; Mern; Purimethol; Purinethiol; Purinethol; Thiopurine; Leupu rin; Mercaptopurin [German]; Mercaptopurina Wellcome; Mercaptopurine anhydrous; Merkaptopuryna [Polish]; Puri Nethol; BW 57 323H; Glaxo Wellcome Brand of 6 Mercaptopurine; GlaxoSmithKline Brand of 6 Mercaptopurine; M0063; NCIMech_000025; PM6; Wellcome Brand of 6 Mercaptopurine; Glaxo Wellcome Brand of 6-Mercaptopurine; GlaxoSmithKline Brand of 6-Mercaptopurine; Mercaptopurina [INN-Spanish]; Mercaptopurine (INN); Mercaptopurine (VAN); Mercaptopurine (anhydrous); Mercaptopurinum [INN-Latin]; Puri-Nethol; Purineantimetabolite: inhibits nucleic acid replication; Purinethol (TN); U-4748; Wellcome Brand of 6-Mercaptopurine; AG-670/31547064; Purine-6-thiol; Leukerin, 99%-Carc; Purine-6(1H)-thione; Purinethol, 6-mercaptopurine, 6-MP, Mercaptopurine; 6 MP; 6 Mercaptopurine Monohydrate; 6 Thiohypoxanthine; 6 Thiopurine; 6-MERCAPTOPURINE MONOHYDRATE; 6-MP; 6-Mercaptopurin; 6-Merkaptopurin; 6-Merkaptopurin [Czech]; 6-Purinethiol; 6-Thiohypoxanthine; 6-Thiopurine; 6-Thioxopurine; Mercaptopurine (Purine analog)
• Indication:
  In total 2 Indication(s)
  Mature B-cell lymphoma [ICD-11: 2A85]; Approved; [1]
  Crohn disease [ICD-11: DD70]; Phase 4; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (3 diseases)
  Acute lymphocytic leukemia [ICD-11: 2B33]; [2]
  Acute myeloid leukemia [ICD-11: 2A60]; [3], [4]
  Inflammatory bowel diseases [ICD-11: DD72]; [5]
• Target: Amidophosphoribosyltransferase (PPAT); PUR1_HUMAN; [1]
• Target: Inosine-5'-monophosphate dehydrogenase 1 (IMPDH1); IMDH1_HUMAN; [1]
• Formula: C5H4N4S
• IsoSMILES: C1=NC2=C(N1)C(=S)N=CN2
• InChI: 1S/C5H4N4S/c10-5-3-4(7-1-6-3)8-2-9-5/h1-2H,(H2,6,7,8,9,10)
• InChIKey: GLVAUDGFNGKCSF-UHFFFAOYSA-N
• PubChem CID: 667490
• ChEBI ID: CHEBI:2208
• TTD Drug ID: D09UZO
• VARIDT ID: DR00145
• INTEDE ID: DR1031
• DrugBank ID: DB01033

Type(s) of Resistant Mechanism of This Drug

  DISM: Drug Inactivation by Structure Modification

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-02: Benign/in-situ/malignant neoplasm

Acute myeloid leukemia [ICD-11: 2A60]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Cytosolic purine 5'-nucleotidase (NT5C2) [3], [4]

• Molecule Alteration: Missense mutation; p.R238W (c.c712t)
• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Next-generation sequencing assay; Exome sequencing assay; Transcriptome sequencing assay; Whole genome sequencing assay; Sanger Sequencing assay
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Several of these alterations are known to induce a more stem cell-like state (eg, IkZF1) or confer resistance directly to specific chemotherapy agents such as CREBBP and glucocorticoids and mutations in the 5-nucleotidase gene NT5C2 and nucleoside a.logs. Many relapse-acquired lesions are enriched in specific pathways, including B-cell development (IkZF1), tumor suppression (TP53),34 Ras signaling, chromatin modification (CREBBP, SETD2),17 and drug metabolism (NT5C2).

Key Molecule: Cytosolic purine 5'-nucleotidase (NT5C2) [3], [4]

• Molecule Alteration: Missense mutation; p.S445F (c.c1334t)
• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Next-generation sequencing assay; Exome sequencing assay; Transcriptome sequencing assay; Whole genome sequencing assay; Sanger Sequencing assay
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Several of these alterations are known to induce a more stem cell-like state (eg, IkZF1) or confer resistance directly to specific chemotherapy agents such as CREBBP and glucocorticoids and mutations in the 5-nucleotidase gene NT5C2 and nucleoside a.logs. Many relapse-acquired lesions are enriched in specific pathways, including B-cell development (IkZF1), tumor suppression (TP53),34 Ras signaling, chromatin modification (CREBBP, SETD2),17 and drug metabolism (NT5C2).

Acute lymphocytic leukemia [ICD-11: 2B33]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Cytosolic purine 5'-nucleotidase (NT5C2) [1]

• Molecule Alteration: Mutation; .
• Resistant Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Genome sequencing assay; Whole-exome sequencing assay
• Mechanism Description: Recent sequencing studies of T-ALL have confirmed the presence of these mutations as well as novel recurrent mutations in the tumor suppressor CNOT3, ribosomal proteins(RPL5 and RPL10) and in the setting of relapse, the NT5C2 gene, which inactivates nucleoside-analogue chemotherapy drugs.

Key Molecule: Cytosolic purine 5'-nucleotidase (NT5C2) [6]

• Molecule Alteration: Missense mutation; p.R367Q
• Resistant Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Exome sequencing assay
• Experiment for Drug Resistance: Conality analyses assay
• Mechanism Description: These two NT5C2 mutations (R367Q, D407V) occur as recurrent mutational hotspots in relapse-ALL and they have been functionally validated. These mutations increase the NT5C2 inosine-5-monophosphate-nucleotidase activity; and therefore lead to resistance to one of the chemotherapeutic drugs, 6-mercaptopurine.

Key Molecule: Cytosolic purine 5'-nucleotidase (NT5C2) [6]

• Molecule Alteration: Missense mutation; p.D407V
• Resistant Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Exome sequencing assay
• Experiment for Drug Resistance: Conality analyses assay
• Mechanism Description: These two NT5C2 mutations (R367Q, D407V) occur as recurrent mutational hotspots in relapse-ALL and they have been functionally validated. These mutations increase the NT5C2 inosine-5-monophosphate-nucleotidase activity; and therefore lead to resistance to one of the chemotherapeutic drugs, 6-mercaptopurine.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: DNA mismatch repair protein Msh6 (MSH6) [2]

• Molecule Alteration: Structural variation; Copy number loss
• Resistant Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Peripheral blood; Blood; Homo sapiens (Human); N.A.
• In Vitro Model: Bone marrow; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Somatic copy number alteration assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Finally, relapse-specific focal deletion of MSH6 and, consequently, reduced gene expression were found in 2 of 20 cases. In an independent cohort of children with ALL, reduced expression of MSH6 was associated with resistance to mercaptopurine and prednisone, thereby providing a plausible mechanism by which this acquired deletion contributes to drug resistance at relapse.

References

• Ref 1: The clonal evolution of leukemic stem cells in T-cell acute lymphoblastic leukemia. Curr Opin Hematol. 2014 Jul;21(4):320-5. doi: 10.1097/MOH.0000000000000058.
• Ref 2: Genome-wide copy number profiling reveals molecular evolution from diagnosis to relapse in childhood acute lymphoblastic leukemia. Blood. 2008 Nov 15;112(10):4178-83. doi: 10.1182/blood-2008-06-165027. Epub 2008 Sep 2.
• Ref 3: Relapse-specific mutations in NT5C2 in childhood acute lymphoblastic leukemia. Nat Genet. 2013 Mar;45(3):290-4. doi: 10.1038/ng.2558. Epub 2013 Feb 3.
• Ref 4: The genomic landscape of acute lymphoblastic leukemia in children and young adults. Hematology Am Soc Hematol Educ Program. 2014 Dec 5;2014(1):174-80. doi: 10.1182/asheducation-2014.1.174. Epub 2014 Nov 18.
• Ref 5: Drug resistance in inflammatory bowel diseases .Curr Opin Pharmacol. 2015 Dec;25:56-61. doi: 10.1016/j.coph.2015.11.003. Epub 2015 Nov 29. 10.1016/j.coph.2015.11.003
• Ref 6: Mutational profiling of acute lymphoblastic leukemia with testicular relapse. J Hematol Oncol. 2017 Mar 2;10(1):65. doi: 10.1186/s13045-017-0434-y.