Inhibition of leukemia-associated transcription factor c-Myb by sesquiterpene lactones and further natural products

The transcription factor c-Myb plays an important role in haematopoiesis, particularly during expansion and self-renewal of immature myeloid and lymphoid progenitor cells. Acute and chronic myeloid leukemia cells depend on the presence of c-Myb for their proliferation and viability and are more sensitive to c-Myb inhibition than their normal counterparts [1]. We recently reported the potential of sesquiterpene lactones (STLs) as first cell-permeable, low-weight inhibitors of the transcription factor c-Myb [2]. Currently, more than 90 different natural substances have been tested as possible c-Myb inhibitors in our GFP-based reporter gene assay. The most active compounds identified so far (two STLs, three Naphthoquinones and two quinone methide triterpenoids) displayed IC₅₀ values <1µM. MTS-Assays were conducted to exclude unspecific cytotoxic effects as mere cause for the observed activity. Analysis of structure-activity relationships revealed alkylation as likely mechanism of action. However, it was shown that the mere capability to react covalently with biomolecules alone is not sufficient for c-Myb inhibition. An ongoing investigation of quantitative structure-activity relationships (QSAR) for more than 50 tested STLs gives insights into structural requirements for strong c-Myb inhibition.

References: [1] Ramsay, R.G. & Gonda, T.J. (2008), Nature Rev. Cancer 8: 523–534 [2] Bujnicki T, Wilczek C, Schomburg C et al. (2012) Leukemia 26, 615–622.