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OHSU # 1295 — Naphthamides as anticancer agents inhibiting CREB-mediated gene transcription

Summary

Researchers at Oregon Health & Science University have developed a first-in-class chemical series that regulates transcription activity of CREB via a novel mechanism of action and has the potential to address an unmet medical need for treatment of multiple cancers. 

Technology Overview

Targeted therapies have demonstrated the ability to effectively halt the progression of many cancers, leading to a global drug market of $93.75 billion in 2020, which is estimated to reach $162 billion by 2028 (Emergen Research, 2021). Cyclic-AMP response element binding protein (CREB) could be a promising target for targeted therapy, since over-expression of this transcription factor results in a poor prognosis for cancer patients and CREB inhibition slows cancer cell growth.

OHSU researchers have developed a novel compound that regulates transcription activity of CREB via a novel mechanism of action. Lead optimization resulted in a first-in-class chemical series that is potent and highly selective. Characterization of these compounds include:

  • High degree of selectivity for CREB and micromolar potency
  • Efficacy at halting in vitro growth of both breast and lung cancer cell types
  • Complete suppression of tumor growth in vivo (see Figure)
  • Absence of signs of toxicity and well-tolerated in vivo

This novel class of molecules show potential as a targeted therapy to address an unmet need for the treatment of patients with prostate cancer, lung cancer, breast cancer and acute myeloid leukemia.

Publications

Xie, F. et al. Identification of a potent inhibitor of CREB-mediated gene transcription with efficacious in vivo anticancer activity. J. of Med Chem, 2015; 58: 5075-5087. Link

Li, B.X. et al. Systemic Inhibition of CREB is well-tolerated in vivo. Sci. Rep. 2016, 6, 34513. Link

Xie, F. et al. Design, synthesis and biological evaluation of regioisomers of 666-115 as inhibitors of CREB-mediated gene transcription. Bioorg Med Chem Lett,  2017; 27: 994-998. Link

Xie, F. et al. Discovery of a synergistic inhibitor of c-AMP-response element binding protein (CREB)-mediated gene transcription with 666-15. J. of Med Chem, 2019; 62:11423-11429. Link

Licensing Opportunity

This technology is available for licensing.

 

 

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