Immunomodulatory drugs (IMiDs), such as pomalidomide, degrade targets by recruitment to cereblon, a protein involved in ubiquitination and proteasome degradation. Here, chemical discovery driven by cereblon recruitment identified small molecule DKY709 as a highly selective degrader of the Treg-associated transcription factor IKZF2 (Helios). In vitro, DKY709 improved PBMC proliferation in Treg coculture, and IFNγ production by exhausted T cells. Oral DKY709 reduced IKZF2 expression in tumors and in blood Tregs in humanized mice, slowing MDA-MB-231 growth. It also decreased IKZF2 in blood Tregs in non-human primates and in patients with solid tumors in an ongoing phase 1 trial.
Contributed by Alex Najibi
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 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.
Author Info: (1) Novartis Institutes for Biomedical Research, Cambridge, MA, USA. Electronic address: simone.bonazzi@novartis.com. (2) Novartis Institutes for Biomedical Research, Cambridge, MA
Author Info: (1) Novartis Institutes for Biomedical Research, Cambridge, MA, USA. Electronic address: simone.bonazzi@novartis.com. (2) Novartis Institutes for Biomedical Research, Cambridge, MA, USA. Electronic address: eva.dhennezel@novartis.com. (3) Novartis Institutes for Biomedical Research, Cambridge, MA, USA. (4) Novartis Institutes for Biomedical Research, Cambridge, MA, USA. (5) Novartis Institutes for Biomedical Research, Cambridge, MA, USA. (6) Novartis Institutes for Biomedical Research, Cambridge, MA, USA. (7) Novartis Institutes for Biomedical Research, Cambridge, MA, USA. (8) Novartis Institutes for Biomedical Research, Cambridge, MA, USA. (9) Novartis Institutes for Biomedical Research, Cambridge, MA, USA. (10) Novartis Institutes for Biomedical Research, Cambridge, MA, USA. (11) Novartis Institutes for Biomedical Research, Cambridge, MA, USA. (12) Novartis Institutes for Biomedical Research, Cambridge, MA, USA. (13) Novartis Institutes for Biomedical Research, Emeryville, CA, USA. (14) Novartis Institutes for Biomedical Research, Emeryville, CA, USA. (15) Novartis Institutes for Biomedical Research, Emeryville, CA, USA. (16) Novartis Institutes for Biomedical Research, Emeryville, CA, USA. (17) Novartis Institutes for Biomedical Research, East Hanover, NJ, USA. (18) Novartis Institutes for Biomedical Research, Cambridge, MA, USA. (19) Novartis Institutes for Biomedical Research, Cambridge, MA, USA. (20) Novartis Institutes for Biomedical Research, Cambridge, MA, USA. (21) Novartis Institutes for Biomedical Research, Cambridge, MA, USA. (22) Novartis Institutes for Biomedical Research, Cambridge, MA, USA. (23) Novartis Institutes for Biomedical Research, Cambridge, MA, USA. (24) Novartis Institutes for Biomedical Research, Cambridge, MA, USA. (25) Novartis Institutes for Biomedical Research, Emeryville, CA, USA. (26) Novartis Institutes for Biomedical Research, Cambridge, MA, USA. (27) Novartis Institutes for Biomedical Research, Cambridge, MA, USA. (28) Novartis Institutes for Biomedical Research, Cambridge, MA, USA. (29) Novartis Institutes for Biomedical Research, Cambridge, MA, USA. (30) Novartis Institutes for Biomedical Research, Cambridge, MA, USA. (31) Novartis Institutes for Biomedical Research, East Hanover, NJ, USA. (32) Novartis Institutes for Biomedical Research, Cambridge, MA, USA. (33) Novartis Institutes for Biomedical Research, Cambridge, MA, USA. (34) Novartis Institutes for Biomedical Research, Cambridge, MA, USA. (35) Novartis Institutes for Biomedical Research, Cambridge, MA, USA. (36) Novartis Institutes for Biomedical Research, Cambridge, MA, USA. (37) Novartis Institutes for Biomedical Research, Cambridge, MA, USA. (38) Novartis Institutes for Biomedical Research, Cambridge, MA, USA. (39) Novartis Institutes for Biomedical Research, Cambridge, MA, USA. (40) Novartis Institutes for Biomedical Research, Cambridge, MA, USA. (41) Novartis Institutes for Biomedical Research, Cambridge, MA, USA. (42) Novartis Institutes for Biomedical Research, Cambridge, MA, USA. (43) Novartis Institutes for Biomedical Research, Cambridge, MA, USA. (44) Novartis Institutes for Biomedical Research, Cambridge, MA, USA. (45) Novartis Institutes for Biomedical Research, Cambridge, MA, USA. Electronic address: jonathan.solomon@novartis.com.
