Showing papers by "Michael B. Sporn published in 2020"
TL;DR: It is shown for the first time that bifunctional CDDO-Im (in contrast toCDDO-Me), as low as 50 nM, can covalently transacylate arginine and serine residues in GSTP and cross link them to adjacent cysteine residues.
Abstract: Synthetic triterpenoids including CDDO, its methyl ester (CDDO-Me, bardoxolone methyl), and its imidazolide (CDDO-Im) enhance Nrf2-mediated antioxidant and anti-inflammatory activity in many diseases by reacting with thiols on the adaptor protein, Keap1. Unlike monofunctional CDDO-Me, the bifunctional analog, CDDO-Im, has a second reactive site (imidazolide) and can covalently bind to amino acids other than cysteine on target proteins such as glutathione S-transferase pi (GSTP), serum albumin, or Keap1. Here we show for the first time that bifunctional CDDO-Im (in contrast to CDDO-Me), as low as 50 nM, can covalently transacylate arginine and serine residues in GSTP and cross-link them to adjacent cysteine residues. Moreover, we show that CDDO-Im binds covalently to Keap1 by forming permanent Michael adducts with eight different cysteines, and acyl adducts with lysine and several tyrosine residues. Modeling studies suggest that the Tyr 85 adduct stabilizes the Keap1-Cul3 complex, thereby enhancing the potency of CDDO-Im.
24 citations
01 Jan 2020
TL;DR: The special relevance of chemoprevention of pancreatic cancer is emphasized, and the importance of the use of combinations of drugs for effective prevention is also stressed.
Abstract: We present a brief review of the history of chemoprevention of cancer, the present status of this field, and its prospects for the future. Topics covered are the scientific basis for chemoprevention of cancer, drugs in current use for chemoprevention of cancer, the need for new synthetic drugs, and the challenges ahead. The special relevance of chemoprevention of pancreatic cancer is emphasized, and the importance of the use of combinations of drugs for effective prevention is also stressed.
3 citations