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Discovery and characterization of a selective IKZF2 glue degrader for cancer immunotherapy.
Bonazzi, Simone; d'Hennezel, Eva; Beckwith, Rohan E J; Xu, Lei; Fazal, Aleem; Magracheva, Anna; Ramesh, Radha; Cernijenko, Artiom; Antonakos, Brandon; Bhang, Hyo-Eun C; Caro, Roxana García; Cobb, Jennifer S; Ornelas, Elizabeth; Ma, Xiaolei; Wartchow, Charles A; Clifton, Matthew C; Forseth, Ry R; Fortnam, Bethany Hughes; Lu, Hongbo; Csibi, Alfredo; Tullai, Jennifer; Carbonneau, Seth; Thomsen, Noel M; Larrow, Jay; Chie-Leon, Barbara; Hainzl, Dominik; Gu, Yi; Lu, Darlene; Meyer, Matthew J; Alexander, Dylan; Kinyamu-Akunda, Jacqueline; Sabatos-Peyton, Catherine A; Dales, Natalie A; Zécri, Frédéric J; Jain, Rishi K; Shulok, Janine; Wang, Y Karen; Briner, Karin; Porter, Jeffery A; Tallarico, John A; Engelman, Jeffrey A; Dranoff, Glenn; Bradner, James E; Visser, Michael; Solomon, Jonathan M.
Afiliación
  • Bonazzi S; Novartis Institutes for Biomedical Research, Cambridge, MA, USA. Electronic address: simone.bonazzi@novartis.com.
  • d'Hennezel E; Novartis Institutes for Biomedical Research, Cambridge, MA, USA. Electronic address: eva.dhennezel@novartis.com.
  • Beckwith REJ; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Xu L; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Fazal A; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Magracheva A; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Ramesh R; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Cernijenko A; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Antonakos B; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Bhang HC; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Caro RG; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Cobb JS; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Ornelas E; Novartis Institutes for Biomedical Research, Emeryville, CA, USA.
  • Ma X; Novartis Institutes for Biomedical Research, Emeryville, CA, USA.
  • Wartchow CA; Novartis Institutes for Biomedical Research, Emeryville, CA, USA.
  • Clifton MC; Novartis Institutes for Biomedical Research, Emeryville, CA, USA.
  • Forseth RR; Novartis Institutes for Biomedical Research, East Hanover, NJ, USA.
  • Fortnam BH; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Lu H; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Csibi A; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Tullai J; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Carbonneau S; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Thomsen NM; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Larrow J; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Chie-Leon B; Novartis Institutes for Biomedical Research, Emeryville, CA, USA.
  • Hainzl D; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Gu Y; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Lu D; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Meyer MJ; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Alexander D; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Kinyamu-Akunda J; Novartis Institutes for Biomedical Research, East Hanover, NJ, USA.
  • Sabatos-Peyton CA; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Dales NA; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Zécri FJ; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Jain RK; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Shulok J; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Wang YK; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Briner K; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Porter JA; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Tallarico JA; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Engelman JA; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Dranoff G; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Bradner JE; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Visser M; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Solomon JM; Novartis Institutes for Biomedical Research, Cambridge, MA, USA. Electronic address: jonathan.solomon@novartis.com.
Cell Chem Biol ; 30(3): 235-247.e12, 2023 03 16.
Article en En | MEDLINE | ID: mdl-36863346
ABSTRACT
Malignant tumors can evade destruction by the immune system by attracting immune-suppressive regulatory T cells (Treg) cells. The IKZF2 (Helios) transcription factor plays a crucial role in maintaining function and stability of Treg cells, and IKZF2 deficiency reduces tumor growth in mice. Here we report the discovery of NVP-DKY709, a selective molecular glue degrader of IKZF2 that spares IKZF1/3. We describe the recruitment-guided medicinal chemistry campaign leading to NVP-DKY709 that redirected the degradation selectivity of cereblon (CRBN) binders from IKZF1 toward IKZF2. Selectivity of NVP-DKY709 for IKZF2 was rationalized by analyzing the DDB1CRBNNVP-DKY709IKZF2(ZF2 or ZF2-3) ternary complex X-ray structures. Exposure to NVP-DKY709 reduced the suppressive activity of human Treg cells and rescued cytokine production in exhausted T-effector cells. In vivo, treatment with NVP-DKY709 delayed tumor growth in mice with a humanized immune system and enhanced immunization responses in cynomolgus monkeys. NVP-DKY709 is being investigated in the clinic as an immune-enhancing agent for cancer immunotherapy.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Factores de Transcripción / Neoplasias Límite: Animals / Humans Idioma: En Revista: Cell Chem Biol Año: 2023 Tipo del documento: Article
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Factores de Transcripción / Neoplasias Límite: Animals / Humans Idioma: En Revista: Cell Chem Biol Año: 2023 Tipo del documento: Article