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Lead compound S007-1235 (anti-colon cancer)

Unique Features of the Molecule:

➤ 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)