Calicheamicin C화학적 특성, 용도, 생산
역사
calicheamicin gamma has been proposed that Alexander the Great was poisoned by drinking the water of the river Mavroneri (identified with the mythological River Styx) which is postulated to have been contaminated by this compound. However, toxicologists believe an extensive knowledge of biological chemistry would have been requisite for any application of this poison in antiquity.
용도
Calicheamicins are a class of enediyne antitumor antibiotics derived from the bacterium Micromonospora echinospora, The main component is calicheamicin γ1. It has strong anti-Gram-positive bacteria activity and anti-tumor effect.
생물학적 활성
Calicheamicin γ1 is an enediyne antitumor antibiotic that acts by binding to DNA and causes strand scission; ADC payload used in development of antibody drug conjugates.
Mechanism of action
Calicheamicins target DNA and cause strand scission. Calicheamicins bind with DNA in the minor groove, wherein they then undergo a reaction analogous to the Bergman cyclization to generate a diradical species. This diradical, 1,4-didehydrobenzene, then abstracts hydrogen atoms from the deoxyribose (sugar) backbone of DNA, which ultimately leads to strand scission.The specificity of binding of calicheamicin to the minor groove of DNA was demonstrated by Crothers et al. (1999) to be due to the aryltetrasaccharide group of the molecule.
in vitro
PF-06647263 (anti-EFNA4-ADC) is generated via conjugation of hE22 lysine residues to the AcButDMH-N-Ac-calicheamicin-γ1 linker-payload with an average drug-to-antibody ratio (DAR) of 4.6. PF-06647263 elicits antigen- and concentration-dependent cytotoxicity, as exposure to PF-06647263 for 96 hours results in cell death (EC 50 = appr 1 ng/mL). CMC-544, consisting of a humanized CD22 Ab linked to calicheamicin, is effective in pediatric primary B-cell precursor acute lymphoblastic leukemia (BCP-ALL) cells in vitro. CMC-544 induces cell death in various ALL cell lines in a dose- and time-dependent way, with IC 50 values ranging from 0.15 to 4.9?ng/mL. CMC-544 (10?ng/mL) is effective and specific in primary BCP-ALL cells. In CMC-544-treated cells, the level of CD22 has decreased relative to that on G5/44-treated cells and continued to decrease.
in vivo
An ADC comprising a humanized anti-EFNA4 monoclonal antibody conjugated to the DNA-damaging agent calicheamicin achieves sustained tumor regressions in both TNBC and ovarian cancer PDX in vivo. PF-06647263 (0.27, 0.36 mg/kg) results in significant tumor regressions in TNBC xenografts.
target
Calicheamicins
참고 문헌
[1] Huryn, D. and P. Wipf. “CHAPTER 5 – Natural product chemistry and anticancer drug discovery.”Cancer Drug Design and Discovery (2008) 107-130.
[2] Berova, N. G. Ellestad and N. Harada. “Characterization by Circular Dichroism Spectroscopy.”Comprehensive Natural Products II (2010): 91-146.
Calicheamicin 준비 용품 및 원자재
원자재
준비 용품
