Calicheamicin

Overview of Calicheamicin

Calicheamicins are a class of enediyne antitumor antibiotics derived from the bacterium Micromonospora echinospora. The most notable compound in this class is calicheamicin γ1, which was originally isolated in the mid-1980s from soil samples in Kerrville, Texas. These compounds are known for their potent antitumor activity, making them some of the most powerful antitumor agents discovered to date. Their mechanism of action involves binding to DNA and causing strand scission, which leads to cell death. Due to their high toxicity, calicheamicins are used in targeted cancer therapies as components of antibody-drug conjugates (ADCs), such as gemtuzumab ozogamicin for acute myeloid leukemia and inotuzumab ozogamicin for B-cell precursor acute lymphoblastic leukemia[1].

Mechanism of Action

Calicheamicins target DNA and cause strand breaks by binding within the minor groove of DNA. This binding triggers a reaction similar to Bergman cyclization, generating a diradical species that abstracts hydrogen atoms from the DNA's sugar backbone, ultimately leading to strand scission. The specificity of this binding is attributed to the aryltetrasaccharide group of the molecule[1].

Biosynthesis

The biosynthesis of calicheamicin involves a type I polyketide synthase (PKS) pathway, which starts with the loading of Acetyl-CoA and the addition of seven Malonyl-CoAs. This growing polyketide chain undergoes modifications by ketoreductase (KR) and dehydratase (DH) domains, followed by processing by accessory enzymes to yield the enediyne core of calicheamicin. Further maturation and glycosylation involve several glycosyltransferases (CalG1-4) and an acyltransferase (CalO4), which recognize specific sugar nucleotides or orsellinic acid substrates[1].

Resistance Mechanism

The bacterium producing calicheamicin, Micromonospora, has developed a self-resistance mechanism to avoid poisoning itself. This involves the cleavage of the protein CalC by calicheamicin, which destroys both the antibiotic and the CalC protein, thereby preventing DNA damage. Structural and functional studies have identified homologs of CalC that may play roles in the biosynthesis and resistance mechanisms[1].

Clinical Use and Development

Calicheamicins have been incorporated into ADCs for targeted cancer therapy. Gemtuzumab ozogamicin (Mylotarg) targets the CD33 antigen for treating acute myeloid leukemia, and inotuzumab ozogamicin (Besponsa) targets CD22 for treating B-cell precursor acute lymphoblastic leukemia. These ADCs deliver the potent cytotoxic effects of calicheamicin to cancer cells while minimizing damage to healthy cells. However, the development and use of these ADCs have faced challenges due to the inherent toxicity of calicheamicin, necessitating careful design to ensure therapeutic efficacy and safety[1].

Conclusion

Calicheamicins represent a powerful class of antitumor antibiotics with a unique mechanism of action based on DNA strand scission. Their potent cytotoxicity has been harnessed in the form of ADCs for targeted cancer therapy, demonstrating the potential of natural products in the development of advanced cancer treatments. Ongoing research aims to improve the therapeutic index of calicheamicin-based therapies, making them safer and more effective for patients.

Citations:

[1] https://en.wikipedia.org/wiki/Calicheamicin

[2] https://www.sciencedirect.com/topics/medicine-and-dentistry/calicheamicin

[3] https://pubs.acs.org/doi/10.1021/ja00051a063

[4] https://pubchem.ncbi.nlm.nih.gov/compound/Calicheamicin

[5] https://pubmed.ncbi.nlm.nih.gov/33722856/

[6] https://onlinelibrary.wiley.com/doi/full/10.1002/tcr.201200005

[7] https://www.sciencedirect.com/topics/nursing-and-health-professions/calicheamicin

[8] https://www.adcreview.com/the-review/cytotoxic-agents/what-is-calicheamicin/

[9] https://pubmed.ncbi.nlm.nih.gov/22711588/

[10] https://www.medchemexpress.com/Calicheamicin.html

[11] https://aacrjournals.org/mct/article/20/6/1112/673238/Calicheamicin-Antibody-Drug-Conjugates-with

[12] https://pubs.acs.org/doi/10.1021/ja00070a005

[13] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4201346/

[14] https://pubmed.ncbi.nlm.nih.gov/9679947/

[15] https://www.sciencedirect.com/topics/chemistry/calicheamicin

[16] https://pubs.acs.org/doi/10.1021/ja00029a030

[17] https://inoue.f.u-tokyo.ac.jp/assets/img/archive-pdf/170902_LS.pdf

[18] https://www.creative-biolabs.com/adc/calicheamicins.htm

[19] https://pubmed.ncbi.nlm.nih.gov/9383371/

[20] https://www.rcsb.org/structure/2PIK