This is a phase I/Ib, open label study. The escalation portion will characterize the safety and tolerability of DKY709 and DKY709 in combination with PDR001 in subjects with NSCLC or melanoma who have received prior anti-PD-1/PD-L1 therapy, or subjects with NPC. After the determination of the MTD/RD for a particular treatment arm, dose expansion will further assess safety, tolerability, PK/PD, and anti-tumor activity of each regimen at the MTD/RD.

Start Date07 May 2019

Sponsor / Collaborator

Novartis Pharmaceuticals Corp.

100 Clinical Results associated with DKY-709

100 Translational Medicine associated with DKY-709

100 Patents (Medical) associated with DKY-709

Literatures (Medical) associated with DKY-709

01 Mar 2023·Cell Chemical Biology

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

Article

Author: Forseth, Ry R ; Tallarico, John A ; Magracheva, Anna ; Xu, Lei ; Hainzl, Dominik ; Fazal, Aleem ; Briner, Karin ; Bhang, Hyo-Eun C ; Beckwith, Rohan E J ; Wartchow, Charles A ; Tullai, Jennifer ; Chie-Leon, Barbara ; Ramesh, Radha ; Zécri, Frédéric J ; Jain, Rishi K ; Csibi, Alfredo ; Wang, Y Karen ; Dranoff, Glenn ; Cobb, Jennifer S ; Lu, Hongbo ; Sabatos-Peyton, Catherine A ; Alexander, Dylan ; d'Hennezel, Eva ; Thomsen, Noel M ; Dales, Natalie A ; Larrow, Jay ; Fortnam, Bethany Hughes ; Carbonneau, Seth ; Gu, Yi ; Clifton, Matthew C ; Caro, Roxana García ; Cernijenko, Artiom ; Bradner, James E ; Bonazzi, Simone ; Visser, Michael ; Ma, Xiaolei ; Porter, Jeffery A ; Engelman, Jeffrey A ; Meyer, Matthew J ; Kinyamu-Akunda, Jacqueline ; Shulok, Janine ; Solomon, Jonathan M ; Lu, Darlene ; Antonakos, Brandon ; Ornelas, Elizabeth

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.

16 Sep 2022·ACS Chemical Biology

Redirecting the Neo-Substrate Specificity of Cereblon-Targeting PROTACs to Helios

Article

Author: Yue, Hong ; Gray, Nathanael S. ; Nowak, Radosław P. ; Verano, Alyssa L. ; Wang, Eric S. ; You, Inchul ; Donovan, Katherine A. ; Fischer, Eric S. ; Mageed, Nada

Immunomodulatory imide drugs (IMiDs), such as thalidomide and its analogues, are some of the most commonly utilized E3 ligase ligands for the development of proteolysis targeting chimeras (PROTACs). While the canonical neo-substrates of IMiDs (i.e., Ikaros and Aiolos) are often considered to be unwanted targets of PROTACs, maintaining the degradation of these neo-substrates also provides the opportunity to synergistically degrade multiple proteins with a single compound. Here, we report the development of ALV-07-082-03, a CDK4/CDK6/Helios triple degrader that consists of palbociclib, an FDA-approved CDK4/6 inhibitor, conjugated to DKY709, a novel IMiD-based Helios degrader. Pharmacological codegradation of CDK4/6 and Helios resulted in potent suppression of downstream signaling and proliferation in cancer cells, as well as enhanced derepression of IL-2 secretion. Thus, not only do we demonstrate the possibility of rationally redirecting the neo-substrate specificity of PROTACs by incorporating alternative molecular glue molecules as E3 ligase ligands but our findings also suggest that cotargeting CDK4/6 and Helios may have synergistic effects.

100 Deals associated with DKY-709

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Advanced Malignant Solid Neoplasm	Phase 1	TW	Novartis Pharmaceuticals Corp.	07 May 2019
Advanced Malignant Solid Neoplasm	Phase 1	ES	Novartis Pharmaceuticals Corp.	07 May 2019
Advanced Malignant Solid Neoplasm	Phase 1	US	Novartis Pharmaceuticals Corp.	07 May 2019
Advanced Malignant Solid Neoplasm	Phase 1	DE	Novartis Pharmaceuticals Corp.	07 May 2019
Advanced Malignant Solid Neoplasm	Phase 1	HK	Novartis Pharmaceuticals Corp.	07 May 2019
Advanced Malignant Solid Neoplasm	Phase 1	JP	Novartis Pharmaceuticals Corp.	07 May 2019
Non-Small Cell Lung Cancer	Phase 1	US	Novartis Pharmaceuticals Corp.	07 May 2019
Non-Small Cell Lung Cancer	Phase 1	TW	Novartis Pharmaceuticals Corp.	07 May 2019
Non-Small Cell Lung Cancer	Phase 1	JP	Novartis Pharmaceuticals Corp.	07 May 2019
Non-Small Cell Lung Cancer	Phase 1	ES	Novartis Pharmaceuticals Corp.	07 May 2019

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