Your browser doesn't support javascript.
loading
Discovery of KT-474─a Potent, Selective, and Orally Bioavailable IRAK4 Degrader for the Treatment of Autoimmune Diseases.
Zheng, Xiaozhang; Ji, Nan; Campbell, Veronica; Slavin, Anthony; Zhu, Xiao; Chen, Dapeng; Rong, Haojing; Enerson, Brad; Mayo, Michele; Sharma, Kirti; Browne, Chris M; Klaus, Christine R; Li, Haoran; Massa, Ginny; McDonald, Alice A; Shi, Yatao; Sintchak, Mike; Skouras, Stephanie; Walther, Dirk M; Yuan, Karen; Zhang, Yi; Kelleher, Joe; Liu, Guang; Luo, Xinbo; Mainolfi, Nello; Weiss, Matthew M.
Afiliación
  • Zheng X; Kymera Therapeutics, 500 N. Beacon Street, Fourth Floor, Watertown, Massachusetts 02472, United States.
  • Ji N; Kymera Therapeutics, 500 N. Beacon Street, Fourth Floor, Watertown, Massachusetts 02472, United States.
  • Campbell V; Kymera Therapeutics, 500 N. Beacon Street, Fourth Floor, Watertown, Massachusetts 02472, United States.
  • Slavin A; Kymera Therapeutics, 500 N. Beacon Street, Fourth Floor, Watertown, Massachusetts 02472, United States.
  • Zhu X; Kymera Therapeutics, 500 N. Beacon Street, Fourth Floor, Watertown, Massachusetts 02472, United States.
  • Chen D; Kymera Therapeutics, 500 N. Beacon Street, Fourth Floor, Watertown, Massachusetts 02472, United States.
  • Rong H; Kymera Therapeutics, 500 N. Beacon Street, Fourth Floor, Watertown, Massachusetts 02472, United States.
  • Enerson B; Kymera Therapeutics, 500 N. Beacon Street, Fourth Floor, Watertown, Massachusetts 02472, United States.
  • Mayo M; Kymera Therapeutics, 500 N. Beacon Street, Fourth Floor, Watertown, Massachusetts 02472, United States.
  • Sharma K; Kymera Therapeutics, 500 N. Beacon Street, Fourth Floor, Watertown, Massachusetts 02472, United States.
  • Browne CM; Kymera Therapeutics, 500 N. Beacon Street, Fourth Floor, Watertown, Massachusetts 02472, United States.
  • Klaus CR; Kymera Therapeutics, 500 N. Beacon Street, Fourth Floor, Watertown, Massachusetts 02472, United States.
  • Li H; Kymera Therapeutics, 500 N. Beacon Street, Fourth Floor, Watertown, Massachusetts 02472, United States.
  • Massa G; Kymera Therapeutics, 500 N. Beacon Street, Fourth Floor, Watertown, Massachusetts 02472, United States.
  • McDonald AA; Kymera Therapeutics, 500 N. Beacon Street, Fourth Floor, Watertown, Massachusetts 02472, United States.
  • Shi Y; Kymera Therapeutics, 500 N. Beacon Street, Fourth Floor, Watertown, Massachusetts 02472, United States.
  • Sintchak M; Kymera Therapeutics, 500 N. Beacon Street, Fourth Floor, Watertown, Massachusetts 02472, United States.
  • Skouras S; Kymera Therapeutics, 500 N. Beacon Street, Fourth Floor, Watertown, Massachusetts 02472, United States.
  • Walther DM; Kymera Therapeutics, 500 N. Beacon Street, Fourth Floor, Watertown, Massachusetts 02472, United States.
  • Yuan K; Kymera Therapeutics, 500 N. Beacon Street, Fourth Floor, Watertown, Massachusetts 02472, United States.
  • Zhang Y; Kymera Therapeutics, 500 N. Beacon Street, Fourth Floor, Watertown, Massachusetts 02472, United States.
  • Kelleher J; Kymera Therapeutics, 500 N. Beacon Street, Fourth Floor, Watertown, Massachusetts 02472, United States.
  • Liu G; Kymera Therapeutics, 500 N. Beacon Street, Fourth Floor, Watertown, Massachusetts 02472, United States.
  • Luo X; Kymera Therapeutics, 500 N. Beacon Street, Fourth Floor, Watertown, Massachusetts 02472, United States.
  • Mainolfi N; Kymera Therapeutics, 500 N. Beacon Street, Fourth Floor, Watertown, Massachusetts 02472, United States.
  • Weiss MM; Kymera Therapeutics, 500 N. Beacon Street, Fourth Floor, Watertown, Massachusetts 02472, United States.
J Med Chem ; 67(20): 18022-18037, 2024 Oct 24.
Article en En | MEDLINE | ID: mdl-39151120
ABSTRACT
Interleukin-1 receptor associated kinase 4 (IRAK4) is an essential mediator of the IL-1R and TLR signaling pathways, both of which have been implicated in multiple autoimmune conditions. Hence, blocking the activity of IRAK4 represents an attractive approach for the treatment of autoimmune diseases. The activity of this serine/threonine kinase is dependent on its kinase and scaffolding activities; thus, degradation represents a potentially superior approach to inhibition. Herein, we detail the exploration of structure-activity relationships that ultimately led to the identification of KT-474, a potent, selective, and orally bioavailable heterobifunctional IRAK4 degrader. This represents the first heterobifunctional degrader evaluated in a nononcology indication and dosed to healthy human volunteers. This molecule successfully completed phase I studies in healthy adult volunteers and patients with atopic dermatitis or hidradenitis suppurativa. Phase II clinical trials in both of these indications have been initiated.
Asunto(s)
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: Enfermedades Autoinmunes / Quinasas Asociadas a Receptores de Interleucina-1 Límite: Adult / Animals / Female / Humans / Male Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
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: Enfermedades Autoinmunes / Quinasas Asociadas a Receptores de Interleucina-1 Límite: Adult / Animals / Female / Humans / Male Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos