Lead compound S007-1235 (anti-colon cancer)
  • Unique Features of the Molecule:

  •  S007-1235 inhibits proliferation and induces apoptosis in cell-lines from breast, colon or haematological malignancies

  •  Inhibits proliferation and induces apoptosis in chronic myelogenous leukemia patient (CML) samples with higher efficacy than marketed drugs Imatinib and Dasatinib.

  •  Mechanism of action is membrane receptor mediated and thus is not likely to be influenced by drug efflux by ABC transporters.
  • Background & Scientific Basis of the Project
  •            S007-1235 is a novel synthetic compound that was identified as a robust anti-cancer agent out of a series of compounds (designed based on commonality of the cytotoxic scaffold of a number of receptor or non-receptor tyrosine kinase inhibitors that are either in market as drugs or are currently undergoing clinical trials) tested for their anti-cancer activities. S007-1235 displayed robust cytotoxicity in cancer cells (cell lines corresponding to both solid tumor and haematological malignancies) while in normal cells its cytotoxic effects were obtained at a much higher dose. S007-1235 induced apoptotic cell death as evident from Annexin V and TUNEL staining. It caused cell growth arrest at the G0-G1 stage of cell cycle. S007-1235 also inhibited cell migration, invasion and angiogenesis in respective breast cancer cellular models. Further, S007-1235 induced cell death in chronic myelogenous leukemia (CML) patient samples, including in CML patient samples harbouring multi-drug resistant T315I mutation in BCR-ABL oncogene. At non-cytotoxic doses S007-1235 caused differentiation of blast cells in cell-lines of CML and acute myelogenous leukemia (AML). While it induced megakaeryocytic differentiation in a CML cell-line (K562), it induced neutrophil differentiation in an AML cell-line (HL-60). This differentiation inducing capacity of S007-1235 was also evident in samples from CML patients in an accelerated phase. Due to the lack of an appropriate leukemia model system, the in vivo efficacy of S007-1235 was tested in an MCF-7 xenograft mouse model, where at a daily oral dose of 16mg/Kg body weight, S007-1235 robustly reduced tumor progression and induced favorable histological changes in the tumors. These histological changes were associated with reduced number or proliferating cells and enhanced TUNEL-positive apoptotic cells in the tumors. Further, S007-1235 also robustly reduced CD133+ colon cancer and ALDH+ breast cancer stem cell population, where its efficacy was comparable to salinomycin, the positive control reagent, used widely as an anti-cancer stem cell experimental agent. Mechanistic analysis of its cytotoxic properties revealed that S007-1235 reduced EGFR and Her2 phosphorylation in breast cancer cells. It suppressed both BCR-ABL and Raf-Rac-ERK pathway in CML cells and activated p38 MAPK. S007-1235-mediated signalings were not due to direct modulation of kinases as it failed to affect the activity of none of the kinases tested in cell-free biochemical assays. S007-1235 also did not directly modulate the activities of any phosphatase. However, S007-1235 treatment was associated with an enhancement of cellular cAMP, and it’s cytotoxic activity could be blocked by pertussis toxin (PTX), indicating that S007-1235 may function through one or more PTX-sensitive G-protein coupled receptors (GPCRs).
  • Together, these data suggest that S007-1235 is a robust anti-cancer agent that specifically causes cell-death in different cancer cells including cancer stem cells. Given that, S007-1235 also induces differentiation of blast cells from haematological malignancies, it appears that this compound may have a robust therapeutic potential in different cancers. Further development of S007-1235 as an anti-cancer agent however is warranted.
  •  Highlights       
  •     
  •  S007-1235 inhibits proliferation and induces apoptosis in cell-lines from breast, colon or haematological malignancies.

  •  S007-1235 inhibits proliferation and induces apoptosis in chronic myelogenous leukemia patient (CML) samples with higher efficacy than marketed drugs Imatinib and Dasatinib.

  •  S007-1235 inhibits proliferation and induces apoptosis in mutant BCR-ABL harbouring patient samples (T315I) refractory to Imatinib or Dasatinib.

  •  S007-1235 reduced breast, colon and leukemia cancer stem cell population and its activity was comparable to Salinomycin, the only experimental reagent capable of inhibiting cancer stem cells.
  •  S007-1235 induced robust myeloid differentiation in leukemia cell-lines as well as blast cells from CML patients in accelerated phase.

  •  Apart from patient samples, S007-1235 also exhibited robust anti-tumor activity in an MCF-7 breast cancer xenograft mouse model.

  •  Detailed mechanistic studies revealed that S007-1235-mediated cell-death in routed through one or more pertussis toxin-sensitive G-protein coupled receptors.

  • Intellectual Property Right Protection (IPR)/ Patent Status   
  •          Patent Title: Novel Aryl Naphthyl methanone oxime derivatives for the treatment of Hematological Malignancies and solid tumors
  • Indian Patent App No. 2567DEL2013 Filed on 30 Aug 2013
  • PCT Application No. PCT/IN2014/000556 Filed on 29-Aug-14
  • Advantage over existing therapeutics   
  • S007-1235 displays clear advantage over existing drugs in terms of its efficacy against drug-resistant cancers by virtue of following observations.
  • Mutations: S007-1235 works on T315I & other BCR-ABL mutant-harboring cells that are refractive to existing therapeutics.
  • Differentiation: Apart from inducing apoptosis, S007-1235 also induces differentiation of CML blasts.    
  • Cancer stem cells: CSCs are root cause of drug resistance and relapse of cancers. S007-1235 shows robust cytotoxicity towards CD34+, CD133+ or ALDH+ CSCs of CML, colon or breast cancer origin. Currently no drug in market is capable of efficiently killing CSCs.
  •  Efflux: S007-1235 mechanism of action is membrane receptor mediated and thus is not likely to be influenced by drug efflux by ABC transporters
  • Inability of immune system in eliminating surviving cancer cells: S007-1235 induces p38 activation. Chance of immunomodulatory action (TH1>TH2 response)