Monomethyl auristatin E

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Monomethyl auristatin E
Monomethylauristatin E.svg
Names
IUPAC name
(S)-N-((3R,4S,5S)-1-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxoheptan-4-yl)-N,3-dimethyl-2-((S)-3-methyl-2-(methylamino)butanamido)butanamide
Other names
Monomethylauristatin E
Identifiers
3D model (JSmol)
AbbreviationsMMAE
ChemSpider
ECHA InfoCard 100.241.825 OOjs UI icon edit-ltr-progressive.svg
KEGG
PubChem CID
UNII
  • InChI=1S/C39H67N5O7/c1-13-25(6)34(43(10)39(49)33(24(4)5)42-38(48)32(40-9)23(2)3)30(50-11)22-31(45)44-21-17-20-29(44)36(51-12)26(7)37(47)41-27(8)35(46)28-18-15-14-16-19-28/h14-16,18-19,23-27,29-30,32-36,40,46H,13,17,20-22H2,1-12H3,(H,41,47)(H,42,48)/t25-,26+,27+,29-,30+,32-,33-,34-,35+,36+/m0/s1 X mark.svgN
    Key: DASWEROEPLKSEI-UIJRFTGLSA-N X mark.svgN
  • InChI=1/C39H67N5O7/c1-13-25(6)34(43(10)39(49)33(24(4)5)42-38(48)32(40-9)23(2)3)30(50-11)22-31(45)44-21-17-20-29(44)36(51-12)26(7)37(47)41-27(8)35(46)28-18-15-14-16-19-28/h14-16,18-19,23-27,29-30,32-36,40,46H,13,17,20-22H2,1-12H3,(H,41,47)(H,42,48)/t25-,26+,27+,29-,30+,32-,33-,34-,35+,36+/m0/s1
    Key: DASWEROEPLKSEI-UIJRFTGLBD
  • CO[C@H]([C@H](C(N[C@@H]([C@H](C1=CC=CC=C1)O)C)=O)C)[C@@]2([H])N(C(C[C@H]([C@H]([C@H](CC)C)N(C)C([C@H](C(C)C)NC([C@@H](NC)C(C)C)=O)=O)OC)=O)CCC2
Properties
C39H67N5O7
Molar mass 717.993 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

Monomethyl auristatin E (MMAE) is a synthetic antineoplastic agent. Because of its toxicity, it cannot be used as a drug itself; instead, it is linked to a monoclonal antibody (MAB) which directs it to the cancer cells. In International Nonproprietary Names for MMAE-MAB-conjugates, the name vedotin refers to MMAE plus its linking structure to the antibody. [1] It is a potent antimitotic drug derived from peptides occurring in marine shell-less mollusc Dolabella auricularia called dolastatins which show potent activity in preclinical studies, both in vitro and in vivo , against a range of lymphomas, leukemia and solid tumors. These drugs show potency of up to 200 times that of vinblastine, another antimitotic drug used for Hodgkin lymphoma as well as other types of cancer. [2]

Contents

MMAE is actually desmethyl-auristatin E; that is, the N-terminal amino group has only one methyl substituent instead of two as in auristatin E itself. [2]

Mechanism of action

Monomethyl auristatin E is an antimitotic agent which inhibits cell division by blocking the polymerisation of tubulin. The linker to the monoclonal antibody is stable in extracellular fluid, but is cleaved by cathepsin once the conjugate has entered a tumor cell, thus activating the antimitotic mechanism. [3] [4]

Structure of a MMAE-MAB-conjugate. The linker, consisting of the amino acids valine (Val) and citrulline (Cit), is cleaved by cathepsin inside tumour cells. The spacer (para-aminobenzylcarbamate) is marked green, the cathepsin-cleavable linker is blue, and the attachment group (consisting of maleimide and caproic acid) is brown. The whole radical inside the four boxes is called vedotin. MMAE-MAB-conjugate skeletal.svg
Structure of a MMAE-MAB-conjugate. The linker, consisting of the amino acids valine (Val) and citrulline (Cit), is cleaved by cathepsin inside tumour cells. The spacer (para-aminobenzylcarbamate) is marked green, the cathepsin-cleavable linker is blue, and the attachment group (consisting of maleimide and caproic acid) is brown. The whole radical inside the four boxes is called vedotin.

Monoclonal antibodies/ADCs

MMAE has been tested with various monoclonal antibodies (usually forming an antibody-drug conjugate).

Examples:

See also

Related Research Articles

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Indusatumab vedotin (MLN-0264) is an antibody-drug conjugate that is under development for the treatment of pancreatic cancer and other gastrointestinal cancers. It consists of a monoclonal antibody (indusatumab) that targets the enzyme guanylate cyclase 2C which is present in some cancers, linked to an average of three to four molecules of the chemotherapeutic agent monomethyl auristatin E (MMAE).

Denintuzumab mafodotin is a humanized monoclonal antibody-drug conjugate designed for the treatment of CD19-positive acute lymphoblastic leukemia and B-cell non-Hodgkin lymphoma. It consists of an anti-CD19 mAb linked to monomethyl auristatin F (MMAF), a cytotoxic agent. This drug was developed by Seattle Genetics.

Depatuxizumab mafodotin is an antibody-drug conjugate designed for the treatment of cancer. It is composed of an EGFR IGg1 monoclonal antibody (depatuxizumab) conjugated to the tubulin inhibitor monomethyl auristatin F via a stable maleimidocaproyl link.

Camidanlumab tesirine is an antibody-drug conjugate (ADC) composed of a human antibody that binds to the protein CD25, conjugated to a pyrrolobenzodiazepine dimer toxin. The experimental drug, developed by ADC Therapeutics is being tested in clinical trials for the treatment of B-cell Hodgkin's lymphoma (HL) and non-Hodgkin lymphoma (NHL), and for the treatment of B-cell acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML).

Cofetuzumab pelidotin is an experimental antibody-drug conjugate in development for the treatment of cancer. It was created by Stemcentrx and is being developed by Pfizer. The drug is an anti-PTK7 monoclonal antibody linked to auristatin-0101, an auristatin microtubule inhibitor.

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Tisotumab vedotin, sold under the brand name Tivdak, is an antibody-drug conjugate used to treat cervical cancer. It is a combination of tisotumab, a monoclonal antibody against tissue factor, and monomethyl auristatin E (MMAE), a potent inhibitor of cell division. It is administered by infusion into a vein.

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References

  1. ↑ Statement on a nonproprietary name adopted by the USAN Council: Vedotin
  2. 1 2 Dosio, F.; Brusa, P.; Cattel, L. (2011). "Immunotoxins and Anticancer Drug Conjugate Assemblies: The Role of the Linkage between Components". Toxins. 3 (12): 848–883. doi: 10.3390/toxins3070848 . PMC   3202854 . PMID   22069744.
  3. 1 2 Seattle Genetics: Brentuximab vedotin (SGN-35) Archived 2011-07-16 at the Wayback Machine
  4. 1 2 Francisco, Joseph A; et al. (2003). "cAC10-vcMMAE, an anti-CD30–monomethyl auristatin E conjugate with potent and selective antitumor activity". Blood. 102 (4): 1458–1465. doi: 10.1182/blood-2003-01-0039 . PMID   12714494. S2CID   25746938.
  5. ↑ A. Klement (13 May 2013). "Sprunginnovation beim Hodgkin-Lymphom: Adcetris". Österreichische Apothekerzeitung (in German) (10/2013): 67f.
  6. ↑ Medical News Today: CuraGen Announces Expansion Of CR011-vcMMAE Phase II Trial In Advanced Breast Cancer
  7. ↑ NCI Drug Dictionary: Glembatumumab vedotin
  8. ↑ Pereira, DS; Guevara, CI; Jin, L; Mbong, N; Verlinsky, A; Hsu, SJ; Aviña, H; Karki, S; Abad, JD; Yang, P; Moon, SJ; Malik, F; Choi, MY; An, Z; Morrison, K; Challita-Eid, PM; Doñate, F; Joseph, IB; Kipps, TJ; Dick, JE; Stover, DR (2015). "AGS67E, an Anti-CD37 Monomethyl Auristatin E Antibody-Drug Conjugate as a Potential Therapeutic for B/T-Cell Malignancies and AML: A New Role for CD37 in AML". Mol Cancer Ther. 14 (7): 1650–60. doi:10.1158/1535-7163.MCT-15-0067. PMC   4557793 . PMID   25934707.
  9. ↑ A study of Escalating Doses of AGS67E Given as Monotherapy in Subjects With Refractory or Relapsed Lymphoid Malignancies
  10. ↑ Coleman, Robert L; Lorusso, Domenica; Gennigens, Christine; González-Martín, Antonio; Randall, Leslie; Cibula, David; Lund, Bente; Woelber, Linn; Pignata, Sandro; Forget, Frederic; Redondo, Andrés (May 2021). "Efficacy and safety of tisotumab vedotin in previously treated recurrent or metastatic cervical cancer (innovaTV 204/GOG-3023/ENGOT-cx6): a multicentre, open-label, single-arm, phase 2 study". The Lancet Oncology. 22 (5): 609–619. doi:10.1016/S1470-2045(21)00056-5. PMID   33845034. S2CID   233223114.
  11. ↑ Indusatumab vedotin (MLN-0264) Clinical Trials. March 2015
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