DKY709 / Novartis - LARVOL DELTA

Crosslinking Profiling of Molecular Glue Degrader-Induced E3 Ligase Interactome to Expand Target Space. (PubMed, Angew Chem Int Ed Engl) - "Our approach presents an efficient and robust strategy for identifying neo-substrates recruited to cereblon E3 ligase by the known degraders CC-885 and DKY709, offering valuable insights for clinical evaluation and significantly expanding their target space. Moreover, we developed two novel MG degraders with potent anti-proliferative effects on cancer cells, and application of our method identified neo-substrates, revealing a previously unrecognized target landscape and advancing our understanding of E3 ligase-neo-substrate interactions. Overall, our study provides a powerful tool for neo-substrate identification and expanding target space of E3 ligase, opening new opportunities for developing next-generation MG degraders to address the clinical challenge of undruggable targets."

Journal • Oncology • Targeted Protein Degradation • CRBN

Study of Safety and Efficacy of DKY709 Alone or in Combination With PDR001 in Patients With Advanced Solid Tumors. (clinicaltrials.gov) - P1 | N=98 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: May 2025 ➔ Sep 2025 | Trial primary completion date: May 2025 ➔ Sep 2025

Trial completion date • Trial primary completion date • Breast Cancer • Colorectal Cancer • Cutaneous Melanoma • Head and Neck Cancer • Lung Cancer • Melanoma • Nasopharyngeal Carcinoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Study of Safety and Efficacy of DKY709 Alone or in Combination With PDR001 in Patients With Advanced Solid Tumors. (clinicaltrials.gov) - P1 | N=98 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Feb 2025 ➔ May 2025 | Trial primary completion date: Feb 2025 ➔ May 2025

Trial completion date • Trial primary completion date • Breast Cancer • Colorectal Cancer • Cutaneous Melanoma • Head and Neck Cancer • Lung Cancer • Melanoma • Nasopharyngeal Carcinoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Study of Safety and Efficacy of DKY709 Alone or in Combination With PDR001 in Patients With Advanced Solid Tumors. (clinicaltrials.gov) - P1 | N=98 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial primary completion date: May 2025 ➔ Dec 2024

Combination therapy • Metastases • Trial primary completion date • Breast Cancer • Colorectal Cancer • Cutaneous Melanoma • Head and Neck Cancer • Lung Cancer • Melanoma • Nasopharyngeal Carcinoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Study of Safety and Efficacy of DKY709 Alone or in Combination With PDR001 in Patients With Advanced Solid Tumors. (clinicaltrials.gov) - P1 | N=98 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Dec 2024 ➔ May 2025 | Trial primary completion date: Dec 2024 ➔ May 2025

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Breast Cancer • Colorectal Cancer • Cutaneous Melanoma • Gastrointestinal Cancer • Head and Neck Cancer • Lung Cancer • Melanoma • Nasopharyngeal Carcinoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Study of Safety and Efficacy of DKY709 Alone or in Combination With PDR001 in Patients With Advanced Solid Tumors. (clinicaltrials.gov) - P1 | N=98 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Sep 2024 ➔ Dec 2024 | Trial primary completion date: Sep 2024 ➔ Dec 2024

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Breast Cancer • Colorectal Cancer • Cutaneous Melanoma • Gastrointestinal Cancer • Head and Neck Cancer • Lung Cancer • Melanoma • Nasopharyngeal Carcinoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Study of Safety and Efficacy of DKY709 Alone or in Combination With PDR001 in Patients With Advanced Solid Tumors. (clinicaltrials.gov) - P1 | N=98 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: May 2025 ➔ Sep 2024 | Trial primary completion date: May 2025 ➔ Sep 2024

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Breast Cancer • Colorectal Cancer • Cutaneous Melanoma • Gastrointestinal Cancer • Lung Cancer • Melanoma • Nasopharyngeal Carcinoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Discovery of highly potent, selective, and orally bioavailable IKZF2 degrader and its anti-tumor activity in syngeneic mouse models (AACR 2024) - "Furthermore, oral administration of PRT-101 exhibits excellent pharmacokinetics, concurrent with IKZF2 degradation, yielding superior anti-tumor effects compared to DKY709 in the MC38 mouse syngeneic model. In conclusion, our findings underscore the potential of the novel IKZF2 degrader as a promising immuno-oncology target for the treatment of solid tumors."

IO biomarker • Preclinical • Oncology • Solid Tumor • CRBN • IKZF1 • IKZF2 • IKZF3 • SALL4

Study of Safety and Efficacy of DKY709 Alone or in Combination With PDR001 in Patients With Advanced Solid Tumors. (clinicaltrials.gov) - P1 | N=98 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Apr 2024 ➔ May 2025 | Trial primary completion date: Apr 2024 ➔ May 2025

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Breast Cancer • Colorectal Cancer • Cutaneous Melanoma • Gastrointestinal Cancer • Lung Cancer • Melanoma • Nasopharyngeal Carcinoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Discovery and optimization of novel CRBN-Mediated molecular glues degraders using recruitment-guided chemistry (ACS-Fall 2023) - "In this presentation, we describe the recruitment-guided medicinal chemistry campaign leading to discovery of NVP-DKY709, a first-in-class selective CRBN glue degrader of IKZF2. In addition to highlighting chemistry efforts that enabled the discovery of NVP-DKY709, we will also focus on chemistry efforts that enabled discovery novel CRBN-dependent DHU (dihydrouracil)-based molecular glue degraders for degradation of variety of proteins."

Targeted Protein Degradation • CRBN • IKZF2

Study of Safety and Efficacy of DKY709 Alone or in Combination With PDR001 in Patients With Advanced Solid Tumors. (clinicaltrials.gov) - P1 | N=99 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: May 2025 ➔ Mar 2024

Trial completion date • Breast Cancer • Colorectal Cancer • Cutaneous Melanoma • Gastrointestinal Cancer • Lung Cancer • Melanoma • Nasopharyngeal Carcinoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Study of Safety and Efficacy of DKY709 Alone or in Combination With PDR001 in Patients With Advanced Solid Tumors. (clinicaltrials.gov) - P1 | N=99 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Mar 2024 ➔ May 2025 | Trial primary completion date: Mar 2024 ➔ May 2025

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Breast Cancer • Colorectal Cancer • Cutaneous Melanoma • Gastrointestinal Cancer • Lung Cancer • Melanoma • Nasopharyngeal Carcinoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Study of Safety and Efficacy of DKY709 Alone or in Combination With PDR001 in Patients With Advanced Solid Tumors. (clinicaltrials.gov) - P1 | N=99 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: May 2025 ➔ Mar 2024 | Trial primary completion date: May 2025 ➔ Mar 2024

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Breast Cancer • Colorectal Cancer • Cutaneous Melanoma • Gastrointestinal Cancer • Lung Cancer • Melanoma • Nasopharyngeal Carcinoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Study of Safety and Efficacy of DKY709 Alone or in Combination With PDR001 in Patients With Advanced Solid Tumors. (clinicaltrials.gov) - P1 | N=99 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Recruiting ➔ Active, not recruiting | N=380 ➔ 99

Combination therapy • Enrollment change • Enrollment closed • Metastases • Breast Cancer • Colorectal Cancer • Cutaneous Melanoma • Gastrointestinal Cancer • Lung Cancer • Melanoma • Nasopharyngeal Carcinoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Discovery and characterization of a selective IKZF2 glue degrader for cancer immunotherapy. (PubMed, Cell Chem Biol) - "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."

Journal • Oncology • Solid Tumor • Targeted Protein Degradation • CRBN • DDB1 • IKZF1 • IKZF2

Study of Safety and Efficacy of DKY709 Alone or in Combination With PDR001 in Patients With Advanced Solid Tumors. (clinicaltrials.gov) - P1 | N=380 | Recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Apr 2024 ➔ May 2025 | Trial primary completion date: Apr 2024 ➔ May 2025

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Breast Cancer • Colorectal Cancer • Cutaneous Melanoma • Gastrointestinal Cancer • Lung Cancer • Melanoma • Nasopharyngeal Carcinoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Redirecting the Neo-Substrate Specificity of Cereblon-Targeting PROTACs to Helios. (PubMed, ACS Chem Biol) - "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)...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."

Journal • Immune Modulation • Inflammation • Oncology • Targeted Protein Degradation • CRBN • IKZF1

Study of Safety and Efficacy of DKY709 Alone or in Combination With PDR001 in Patients With Advanced Solid Tumors. (clinicaltrials.gov) - P1 | N=380 | Recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Apr 2023 ➔ Apr 2024 | Trial primary completion date: Apr 2023 ➔ Apr 2024

Combination therapy • Trial completion date • Trial primary completion date • Breast Cancer • Colorectal Cancer • Cutaneous Melanoma • Gastrointestinal Cancer • Lung Cancer • Melanoma • Nasopharyngeal Carcinoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

NVP-DKY709, a clinical-stage molecular glue degrader of Helios/IKZF2 modulating tumor T-cell biology (AACR 2022) - "There is no abstract associated with this presentation."

Clinical • Oncology • IKZF2

Discovery and characterization of NVP-DKY709: A first-in-class selective IKZF2 glue degrader (AACR 2022) - "There is no abstract associated with this presentation."

Oncology • IKZF2

Study of Safety and Efficacy of DKY709 Alone or in Combination With PDR001 in Patients With Advanced Solid Tumors. (clinicaltrials.gov) - P1; N=320; Recruiting; Sponsor: Novartis Pharmaceuticals; Trial completion date: Nov 2022 ➔ Apr 2023; Trial primary completion date: Nov 2022 ➔ Apr 2023

Clinical • Combination therapy • Trial completion date • Trial primary completion date • Breast Cancer • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Melanoma • Nasopharyngeal Carcinoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer