Monomethyl auristatin F

Last updated
Monomethyl auristatin F
Monomethylauristatin F.svg
Names
IUPAC name
(S)-2-((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((S)-N,3-dimethyl-2-((S)-3-methyl-2-(methylamino)butanamido)butanamido)-3-methoxy-5-methylheptanoyl)pyrrolidin-2-yl)-3-methoxy-2-methylpropanamido)-3-phenylpropanoic acid
Identifiers
  • 745017-94-1 Yes check.svgY
3D model (JSmol)
AbbreviationsMMAF
ChemSpider
PubChem CID
UNII
  • InChI=1S/C39H65N5O8/c1-12-25(6)34(43(9)38(48)33(24(4)5)42-37(47)32(40-8)23(2)3)30(51-10)22-31(45)44-20-16-19-29(44)35(52-11)26(7)36(46)41-28(39(49)50)21-27-17-14-13-15-18-27/h13-15,17-18,23-26,28-30,32-35,40H,12,16,19-22H2,1-11H3,(H,41,46)(H,42,47)(H,49,50)/t25-,26+,28-,29-,30+,32-,33-,34-,35+/m0/s1
    Key: MFRNYXJJRJQHNW-DEMKXPNLSA-N
  • InChI=1/C39H65N5O8/c1-12-25(6)34(43(9)38(48)33(24(4)5)42-37(47)32(40-8)23(2)3)30(51-10)22-31(45)44-20-16-19-29(44)35(52-11)26(7)36(46)41-28(39(49)50)21-27-17-14-13-15-18-27/h13-15,17-18,23-26,28-30,32-35,40H,12,16,19-22H2,1-11H3,(H,41,46)(H,42,47)(H,49,50)/t25-,26+,28-,29-,30+,32-,33-,34-,35+/m0/s1
    Key: MFRNYXJJRJQHNW-DEMKXPNLBL
  • O=C(N2[C@H]([C@H](OC)[C@H](C(=O)N[C@H](C(=O)O)Cc1ccccc1)C)CCC2)C[C@@H](OC)[C@@H](N(C(=O)[C@@H](NC(=O)[C@@H](NC)C(C)C)C(C)C)C)[C@@H](C)CC
Properties
C39H65N5O8
Molar mass 731.976 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

Monomethyl auristatin F (MMAF) is a synthetic antineoplastic agent. [1] It is part of the approved drug belantamab mafodotin in multiple myeloma and some experimental anti-cancer antibody-drug conjugates such as vorsetuzumab mafodotin and SGN-CD19A. In International Nonproprietary Names for MMAF-antibody-conjugates, the name mafodotin refers to MMAF plus its attachment structure to the antibody. [2]

Contents

Mechanism of action

Monomethyl auristatin F is an antimitotic agent which inhibits cell division by blocking the polymerisation of tubulin. It is linked to an antibody with high affinity to structures on cancer cells, causing MMAF to accumulate in such cells. [3]

Chemistry

MMAF is actually desmethyl-auristatin F; that is, the N-terminal amino group has only one methyl substituent instead of two as in auristatin F itself. [3]

Structure of conjugate of MMAF with a monoclonal antibody (MAB). The attachment group consists of maleimide and caproic acid. About eight such structures are bound to a single antibody molecule. MMAF-MAB-conjugate skeletal.svg
Structure of conjugate of MMAF with a monoclonal antibody (MAB). The attachment group consists of maleimide and caproic acid. About eight such structures are bound to a single antibody molecule.

See also

Related Research Articles

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Monomethyl auristatin E Chemical compound

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. 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.

Antibody-drug conjugate

Antibody-drug conjugates or ADCs are a class of biopharmaceutical drugs designed as a targeted therapy for treating cancer. Unlike chemotherapy, ADCs are intended to target and kill tumor cells while sparing healthy cells. As of 2019, some 56 pharmaceutical companies were developing ADCs.

Gene expression profiling has revealed that diffuse large B-cell lymphoma (DLBCL) is composed of at least 3 different sub-groups, each having distinct oncogenic mechanisms that respond to therapies in different ways. Germinal Center B-Cell like (GCB) DLBCLs appear to arise from normal germinal center B cells, while Activated B-cell like (ABC) DLBCLs are thought to arise from postgerminal center B cells that are arrested during plasmacytic differentiation. The differences in gene expression between GCB DLBCL and ABC DLBCL are as vast as the differences between distinct types of leukemia, but these conditions have historically been grouped together and treated as the same disease.

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Vorsetuzumab mafodotin (SGN-75) is an antibody-drug conjugate (ADC) directed to the protein CD70 designed for the treatment of cancer. It is a humanized monoclonal antibody, vorsetuzumab, conjugated with noncleavable monomethyl auristatin F (MMAF), a cytotoxic agent.

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Isatuximab

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Melphalan flufenamide

Melphalan flufenamide, sold under the brand name Pepaxto, is an anticancer medication used to treat multiple myeloma.

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.

Rovalpituzumab tesirine (Rova-T) is an experimental antibody-drug conjugate targeting the protein DLL3 on tumor cells. It was originally developed by Stemcentrx and was purchased by AbbVie. It was tested for use in small-cell lung cancer, but development was terminated after unsuccessful phase III trial.

Belantamab mafodotin, sold under the brand name Blenrep, is a medication for the treatment of relapsed and refractory multiple myeloma.

Idecabtagene vicleucel, sold under the brand name Abecma, is a cell-based gene therapy to treat multiple myeloma.

References

  1. ↑ Tai, Y. T.; Mayes, P. A.; Acharya, C; Zhong, M. Y.; Cea, M; Cagnetta, A; Craigen, J; Yates, J; Gliddon, L; Fieles, W; Hoang, B; Tunstead, J; Christie, A. L.; Kung, A. L.; Richardson, P; Munshi, N. C.; Anderson, K. C. (2014). "Novel afucosylated anti-B cell maturation antigen-monomethyl auristatin F antibody-drug conjugate (GSK2857916) induces potent and selective anti-multiple myeloma activity". Blood. 123 (20): 3128–38. doi:10.1182/blood-2013-10-535088. PMC   4023420 . PMID   24569262.
  2. ↑ Statement on a nonproprietary name adopted by the USAN Council: Mafodotin
  3. 1 2 3 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.
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