Discovery and characterization of a selective IKZF2 glue degrader for cancer immunotherapy

被引：75

作者：

Bonazzi, Simone ^{[1
]}

d'Hennezel, Eva ^{[1
]}

Beckwith, Rohan E. J. ^{[1
]}

Xu, Lei ^{[1
]}

Fazal, Aleem ^{[1
]}

Magracheva, Anna ^{[1
]}

Ramesh, Radha ^{[1
]}

Cernijenko, Artiom ^{[1
]}

Antonakos, Brandon ^{[1
]}

Bhang, Hyo-eun C. ^{[1
]}

Caro, Roxana Garcia ^{[1
]}

Cobb, Jennifer S. ^{[1
]}

Ornelas, Elizabeth ^{[2
]}

Ma, Xiaolei ^{[2
]}

Wartchow, Charles A. ^{[2
]}

Clifton, Matthew C. ^{[1
,2
]}

Forseth, Ry R. ^{[3
]}

Fortnam, Bethany Hughes ^{[1
]}

Lu, Hongbo ^{[1
]}

Csibi, Alfredo ^{[1
]}

Tullai, Jennifer ^{[1
]}

Carbonneau, Seth ^{[1
]}

Thomsen, Noel M. ^{[1
]}

Larrow, Jay ^{[1
]}

Chie-Leon, Barbara ^{[2
]}

Hainzl, Dominik ^{[1
]}

Gu, Yi ^{[1
]}

Lu, Darlene ^{[1
]}

Meyer, Matthew J. ^{[1
]}

Alexander, Dylan ^{[1
]}

Kinyamu-Akunda, Jacqueline ^{[3
]}

Sabatos-Peyton, Catherine A. ^{[1
]}

Dales, Natalie A. ^{[1
]}

Zecri, Frederic J. ^{[1
]}

Jain, Rishi K. ^{[1
]}

Shulok, Janine ^{[1
]}

Wang, Y. Karen ^{[1
]}

Briner, Karin ^{[1
]}

Porter, Jeffery A. ^{[1
]}

Tallarico, John A. ^{[1
]}

Engelman, Jeffrey A. ^{[1
]}

Dranoff, Glenn ^{[1
]}

Bradner, James E. ^{[1
]}

Visser, Michael ^{[1
]}

Solomon, Jonathan M. ^{[1
]}

机构：

[1] Novartis Inst Biomed Res, Cambridge, MA 02139 USA

[2] Novartis Inst Biomed Res, Emeryville, CA USA

[3] Novartis Inst Biomed Res, E Hanover, NJ USA

来源：

CELL CHEMICAL BIOLOGY | 2023年 / 30卷 / 03期

关键词：

REGULATORY T-CELLS; BETA-GALACTOSIDASE COMPLEMENTATION; DEGRADATION; DYSFUNCTION; COMPLEX; TARGET;

D O I：

10.1016/j.chembiol.2023.02.005

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Malignant tumors can evade destruction by the immune system by attracting immune-suppressive regulato-ry 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 recruit-ment-guided medicinal chemistry campaign leading to NVP-DKY709 that redirected the degradation selec-tivity of cereblon (CRBN) binders from IKZF1 toward IKZF2. Selectivity of NVP-DKY709 for IKZF2 was ratio-nalized by analyzing the DDB1:CRBN:NVP-DKY709:IKZF2(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.

引用

页码：235 / +

页数：26

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