Wednesday, April 29, 2015

Drugs in Clinical Pipeline: SCR7

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.

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.