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Phenotypic screen identifies calcineurin-sparing FK506 analogs as BMP potentiators for treatment of acute kidney injury.
Larraufie, Marie-Hélène; Gao, Xiaolin; Xia, Xiaobo; Devine, Patrick J; Kallen, Joerg; Liu, Dong; Michaud, Gregory; Harsch, Andreas; Savage, Nik; Ding, Jian; Tan, Kian; Mihalic, Manuel; Roggo, Silvio; Canham, Stephen M; Bushell, Simon M; Krastel, Philipp; Gao, Jinhai; Izaac, Aude; Altinoglu, Erhan; Lustenberger, Philipp; Salcius, Michael; Harbinski, Fred; Williams, Eric T; Zeng, Liling; Loureiro, Joseph; Cong, Feng; Fryer, Christy J; Klickstein, Lloyd; Tallarico, John A; Jain, Rishi K; Rothman, Deborah M; Wang, Shaowen.
Afiliación
  • Larraufie MH; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Gao X; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Xia X; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Devine PJ; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Kallen J; Novartis Institutes for Biomedical Research, Basel, Switzerland.
  • Liu D; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Michaud G; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Harsch A; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Savage N; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Ding J; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Tan K; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Mihalic M; Novartis Institutes for Biomedical Research, Basel, Switzerland.
  • Roggo S; Novartis Institutes for Biomedical Research, Basel, Switzerland.
  • Canham SM; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Bushell SM; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Krastel P; Novartis Institutes for Biomedical Research, Basel, Switzerland.
  • Gao J; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Izaac A; Novartis Institutes for Biomedical Research, Basel, Switzerland.
  • Altinoglu E; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Lustenberger P; Novartis Global Drug Development, Basel, Switzerland.
  • Salcius M; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Harbinski F; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Williams ET; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Zeng L; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Loureiro J; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Cong F; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Fryer CJ; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Klickstein L; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Tallarico JA; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Jain RK; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Rothman DM; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Wang S; Novartis Institutes for Biomedical Research, Cambridge, MA, USA. Electronic address: shaowen.wang@novartis.com.
Cell Chem Biol ; 28(9): 1271-1282.e12, 2021 09 16.
Article en En | MEDLINE | ID: mdl-33894161
Acute kidney injury (AKI) is a life-threatening disease with no known curative or preventive therapies. Data from multiple animal models and human studies have linked dysregulation of bone morphogenetic protein (BMP) signaling to AKI. Small molecules that potentiate endogenous BMP signaling should have a beneficial effect in AKI. We performed a high-throughput phenotypic screen and identified a series of FK506 analogs that act as potent BMP potentiators by sequestering FKBP12 from BMP type I receptors. We further showed that calcineurin inhibition was not required for this activity. We identified a calcineurin-sparing FK506 analog oxtFK through late-stage functionalization and structure-guided design. OxtFK demonstrated an improved safety profile in vivo relative to FK506. OxtFK stimulated BMP signaling in vitro and in vivo and protected the kidneys in an AKI mouse model, making it a promising candidate for future development as a first-in-class therapeutic for diseases with dysregulated BMP signaling.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Tacrolimus / Proteínas Morfogenéticas Óseas / Lesión Renal Aguda Límite: Animals / Humans / Male Idioma: En Revista: Cell Chem Biol Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
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XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Tacrolimus / Proteínas Morfogenéticas Óseas / Lesión Renal Aguda Límite: Animals / Humans / Male Idioma: En Revista: Cell Chem Biol Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos