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

被引：56

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

共 60 条

[1] Arista L., 2021, BIFUNCTIONAL DEGRADE, P1
[2] Helios Induces Epigenetic Silencing of Il2 Gene Expression in Regulatory T Cells
Baine, Ian
Basu, Samik
Ames, Rachel
Sellers, Rani S.
Macian, Fernando
[J]. JOURNAL OF IMMUNOLOGY, 2013, 190 (03) : 1008 - 1016
[3] Dominant-negative IKZF1 mutations cause a T, B, and myeloid cell combined immunodeficiency
Boutboul, David
Kuehn, Hye Sun
de Wyngaert, Zoe Van
Niemela, Julie E.
Callebaut, Isabelle
Stoddard, Jennifer
Lenoir, Christelle
Barlogis, Vincent
Farnarier, Catherine
Vely, Frederic
Yoshida, Nao
Kojima, Seiji
Kanegane, Hirokazu
Hoshino, Akihiro
Hauck, Fabian
Lhermitte, Ludovic
Asnafi, Vahid
Roehrs, Philip
Chen, Shaoying
Verbsky, James W.
Calvo, Katherine R.
Husami, Ammar
Zhang, Kejian
Roberts, Joseph
Amrol, David
Sleaseman, John
Hsu, Amy P.
Holland, Steven M.
Marsh, Rebecca
Fischer, Alain
Fleisher, Thomas A.
Picard, Capucine
Latour, Sylvain
Rosenzweig, Sergio D.
[J]. JOURNAL OF CLINICAL INVESTIGATION, 2018, 128 (07) : 3071 - 3087
[4] Helios Deficiency Has Minimal Impact on T Cell Development and Function
Cai, Qi
Dierich, Andree
Oulad-Abdelghani, Mustapha
Chan, Susan
Kastner, Philippe
[J]. JOURNAL OF IMMUNOLOGY, 2009, 183 (04) : 2303 - 2311
[5] Evolution of Cereblon-Mediated Protein Degradation as a Therapeutic Modality
Chamberlain, Philip P.
D'Agostino, Laura A.
Ellis, J. Michael
Hansen, Joshua D.
Matyskiela, Mary E.
McDonald, Joseph J.
Riggs, Jennifer R.
Hamann, Lawrence G.
[J]. ACS MEDICINAL CHEMISTRY LETTERS, 2019, 10 (12): : 1592 - 1602
[6] Structure of the human Cereblon-DDB1-lenalidomide complex reveals basis for responsiveness to thalidomide analogs
Chamberlain, Philip P.
Lopez-Girona, Antonia
Miller, Karen
Carmel, Gilles
Pagarigan, Barbra
Chie-Leon, Barbara
Rychak, Emily
Corral, Laura G.
Ren, Yan J.
Wang, Maria
Riley, Mariko
Delker, Silvia L.
Ito, Takumi
Ando, Hideki
Mori, Tomoyuki
Hirano, Yoshinori
Handa, Hiroshi
Hakoshima, Toshio
Daniel, Thomas O.
Cathers, Brian E.
[J]. NATURE STRUCTURAL & MOLECULAR BIOLOGY, 2014, 21 (09) : 803 - 809
[7] Molecular and Transcriptional Basis of CD4+ T Cell Dysfunction during Chronic Infection
Crawford, Alison
Angelosanto, Jill M.
Kao, Charlly
Doering, Travis A.
Odorizzi, Pamela M.
Barnett, Burton E.
Wherry, E. John
[J]. IMMUNITY, 2014, 40 (02) : 289 - 302
[8] Drugging the 'undruggable' cancer targets
Dang, Chi V.
Reddy, E. Premkumar
Shokat, Kevan M.
Soucek, Laura
[J]. NATURE REVIEWS CANCER, 2017, 17 (08) : 502 - 508
[9] NanoLuc Complementation Reporter Optimized for Accurate Measurement of Protein Interactions in Cells
Dixon, Andrew S.
Schwinn, Marie K.
Hall, Mary P.
Zimmerman, Kris
Otto, Paul
Lubben, Thomas H.
Butler, Braeden L.
Binkowski, Brock F.
Machleidt, Thomas
Kirkland, Thomas A.
Wood, Monika G.
Eggers, Christopher T.
Encell, Lance P.
Wood, Keith V.
[J]. ACS CHEMICAL BIOLOGY, 2016, 11 (02) : 400 - 408
[10] Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane Radial Ray syndrome
Donovan, Katherine A.
An, Jian
Nowak, Radoslaw P.
Yuan, Jingting C.
Fink, Emma C.
Berry, Bethany C.
Ebert, Benjamin L.
Fischer, Eric S.
[J]. ELIFE, 2018, 7

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