SCR7 [5,6-bis((E)-benzylideneamino)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one] is a
novel anti-cancer molecule that is a potent inhibitor of a DNA repair pathway
known as non-homologous end-joining (NHEJ). DNA Ligase IV is responsible for
sealing of double-strand breaks (DSBs) during nonhomologous end-joining (NHEJ).
Inhibiting Ligase IV could result in amassing of DSBs, thereby serving as a
strategy toward treatment of cancer. SCR7 inhibits joining of DSBs in cell-free
repair system. SCR7 blocks Ligase IV-mediated joining by interfering with its
DNA binding but not that of T4 DNA Ligase or Ligase I.
SCR7 inhibits
NHEJ in a Ligase IV-dependent manner within cells, and activates the intrinsic
apoptotic pathway. More importantly, SCR7 impedes tumor progression in mouse
models and when coadministered with DSB-inducing therapeutic modalities enhance
their sensitivity significantly. This inhibitor to target NHEJ offers a
strategy toward the treatment of cancer and improvement of existing regimens
[1].
SCR7 is
developed by Department of Biochemistry, Indian Institute of Science, Bangalore,
India.
Common Name: SCR7
Synonyms: PFK SCR7;
SCR-7; SCR 7
IUPAC Name: 5,6-bis((E)-benzylideneamino)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one
CAS Number: 1533426-72-0
Mechanism of Action: DNA Ligase Inhibitor; DNA Ligase IV
Inhibitor
Indication: Various Cancers
Development Stage: Investigational
Company: Indian
Institute of Science
The
hydrophobicity of SCR7 decreases its bioavailability which is a major setback
in the utilization of this compound as a therapeutic agent. In order to
circumvent the drawback of SCR7, we prepared a polymer encapsulated form of
SCR7. The physical interaction of SCR7 and Pluronic® copolymer is evident from
different analytical techniques. The in vitro cytotoxicity of the drug
formulations is established using the MTT assay [2].
Radiation
therapy and chemotherapy leads to DSB where NHEJ plays a major role in
providing resistance to these agents in a cancer cell. The initial inhibitor
L189 against Ligase I, III and IV reported in literature was non-specific. Researchers
at IISc (Indian Institute of Science) overcame this limitation by targeted
design using specific docking of Ligase IV and comparing with L189. The clever
strategy led to the discovery of a novel specific inhibitor SCR7 for Ligase IV.
Using elegant experiments on cell lines and mouse model the authors
convincingly demonstrated that SCR7 was a specific Ligase IV inhibitor. SCR7
inhibits end joining of double strand breaks in diverse cell types resulting in
tumour regression by activation of p53 mediated apoptosis. Notably SCR7
treatment did not result in any adverse effects in mice and did not inhibit
Ligase III [3].
SCR7 appears
to be a potential cytotoxic anti-cancer drug candidate that can be used either
alone or in combination with conventional DNA damaging drugs, owing to its
specificity and absence of adverse effects in mice model. However, the effect
of SCR7 in base excision repair needs to be studied. Moreover, although SCR7 is
a promising anti-cancer drug, it is likely that it may not be effective in
tumours with Ligase IV mutations, or inactive p53, or mutated ATM. It may be
necessary to study the mutation profile of Ligase IV in diverse cancers to
foresee the application of SCR7 as a therapeutic agent.
References:
1. Srivastava, M.; et. al. An inhibitor of
nonhomologous end-joining abrogates double-strand break repair and impedes
cancer progression. Cell 2012, 151(7), 1474-1487.
2. John, F.; et. al.
Pluronic copolymer encapsulated SCR7 as a potential anticancer agent. Faraday
Discuss 2015, 177, 155-161.
3. Kotnis,
A.; et. al. Novel inhibitor of DNA
ligase IV with a promising cancer therapeutic potential. J Biosci 2014, 39(3), 339-340.
