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Engineering Hydroxylase Activity, Selectivity, and Stability for a Scalable Concise Synthesis of a Key Intermediate to Belzutifan.
Cheung-Lee, Wai Ling; Kolev, Joshua N; McIntosh, John A; Gil, Agnieszka A; Pan, Weilan; Xiao, Li; Velásquez, Juan E; Gangam, Rekha; Winston, Matthew S; Li, Shasha; Abe, Kotoe; Alwedi, Embarek; Dance, Zachary E X; Fan, Haiyang; Hiraga, Kaori; Kim, Jungchul; Kosjek, Birgit; Le, Diane N; Marzijarani, Nastaran Salehi; Mattern, Keith; McMullen, Jonathan P; Narsimhan, Karthik; Vikram, Ajit; Wang, Wei; Yan, Jia-Xuan; Yang, Rong-Sheng; Zhang, Victoria; Zhong, Wendy; DiRocco, Daniel A; Morris, William J; Murphy, Grant S; Maloney, Kevin M.
Afiliación
  • Cheung-Lee WL; Process Research and Development, Merck & Co., Inc., Rahway, NJ 07065, USA.
  • Kolev JN; Process Research and Development, Merck & Co., Inc., Rahway, NJ 07065, USA.
  • McIntosh JA; Process Research and Development, Merck & Co., Inc., Rahway, NJ 07065, USA.
  • Gil AA; Process Research and Development, Merck & Co., Inc., Rahway, NJ 07065, USA.
  • Pan W; Process Research and Development, Merck & Co., Inc., Rahway, NJ 07065, USA.
  • Xiao L; Modeling & Informatics, Discovery Chemistry, Merck & Co., Inc., Rahway, NJ 07065, USA.
  • Velásquez JE; Process Research and Development, Merck & Co., Inc., Rahway, NJ 07065, USA.
  • Gangam R; Analytical Research and Development, Merck & Co., Inc., Rahway, NJ 07065, USA.
  • Winston MS; Process Research and Development, Merck & Co., Inc., Rahway, NJ 07065, USA.
  • Li S; Analytical Research and Development, Merck & Co., Inc., Rahway, NJ 07065, USA.
  • Abe K; Chemical Commercialization Technologies, Merck & Co., Inc., Rahway, NJ 07065, USA.
  • Alwedi E; Process Research and Development, Merck & Co., Inc., Rahway, NJ 07065, USA.
  • Dance ZEX; Analytical Research and Development, Merck & Co., Inc., Rahway, NJ 07065, USA.
  • Fan H; API Process Research & Development (Biocatalysis), Shanghai STA Pharmaceutical Co., Ltd., Shanghai, 201507, China.
  • Hiraga K; Process Research and Development, Merck & Co., Inc., Rahway, NJ 07065, USA.
  • Kim J; Process Research and Development, Merck & Co., Inc., Rahway, NJ 07065, USA.
  • Kosjek B; Process Research and Development, Merck & Co., Inc., Rahway, NJ 07065, USA.
  • Le DN; Process Research and Development, Merck & Co., Inc., Rahway, NJ 07065, USA.
  • Marzijarani NS; Process Research and Development, Merck & Co., Inc., Rahway, NJ 07065, USA.
  • Mattern K; Process Research and Development, Merck & Co., Inc., Rahway, NJ 07065, USA.
  • McMullen JP; Process Research and Development, Merck & Co., Inc., Rahway, NJ 07065, USA.
  • Narsimhan K; Process Research and Development, Merck & Co., Inc., Rahway, NJ 07065, USA.
  • Vikram A; Process Research and Development, Merck & Co., Inc., Rahway, NJ 07065, USA.
  • Wang W; API Process Research & Development (Biocatalysis), Shanghai STA Pharmaceutical Co., Ltd., Shanghai, 201507, China.
  • Yan JX; Analytical Research and Development, Merck & Co., Inc., Rahway, NJ 07065, USA.
  • Yang RS; Analytical Research and Development, Merck & Co., Inc., Rahway, NJ 07065, USA.
  • Zhang V; Process Research and Development, Merck & Co., Inc., Rahway, NJ 07065, USA.
  • Zhong W; Analytical Research and Development, Merck & Co., Inc., Rahway, NJ 07065, USA.
  • DiRocco DA; Process Research and Development, Merck & Co., Inc., Rahway, NJ 07065, USA.
  • Morris WJ; Process Research and Development, Merck & Co., Inc., Rahway, NJ 07065, USA.
  • Murphy GS; Process Research and Development, Merck & Co., Inc., Rahway, NJ 07065, USA.
  • Maloney KM; Process Research and Development, Merck & Co., Inc., Rahway, NJ 07065, USA.
Angew Chem Int Ed Engl ; 63(13): e202316133, 2024 03 22.
Article en En | MEDLINE | ID: mdl-38279624
ABSTRACT
Biocatalytic oxidations are an emerging technology for selective C-H bond activation. While promising for a range of selective oxidations, practical use of enzymes catalyzing aerobic hydroxylation is presently limited by their substrate scope and stability under industrially relevant conditions. Here, we report the engineering and practical application of a non-heme iron and α-ketoglutarate-dependent dioxygenase for the direct stereo- and regio-selective hydroxylation of a non-native fluoroindanone en route to the oncology treatment belzutifan, replacing a five-step chemical synthesis with a direct enantioselective hydroxylation. Mechanistic studies indicated that formation of the desired product was limited by enzyme stability and product overoxidation, with these properties subsequently improved by directed evolution, yielding a biocatalyst capable of >15,000 total turnovers. Highlighting the industrial utility of this biocatalyst, the high-yielding, green, and efficient oxidation was demonstrated at kilogram scale for the synthesis of belzutifan.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Oxigenasas de Función Mixta / Indenos Idioma: En Revista: Angew Chem Int Ed Engl Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Alemania
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Oxigenasas de Función Mixta / Indenos Idioma: En Revista: Angew Chem Int Ed Engl Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Alemania