P1/2, N=32, Not yet recruiting, University of Aarhus

The original molecular glue degraders (thalidomide, lenalidomide, and pomalidomide) are known to bind to cereblon (CRBN) and alter its surface to induce recruitment, ubiquitination, and degradation of therapeutically valuable neosubstrates (IKZF1, IKZF3, and CK1α). Herein, we describe the medicinal chemistry efforts that resulted in the discovery of SJ3149 as well as other potent and selective CK1α degraders. We report kinetic profiling and parameters of CK1α degradation, ternary complex, antiproliferative effects, in vitro ADME data, and in vivo pharmacokinetic studies with demonstrated oral bioavailability.

P1, N=8, Terminated, Exeliom Biosciences | Active, not recruiting --> Terminated; Due to low recruitment

These observations imply that Pomalidomide treatment influences the T-cell repertoire, particularly in the CD4 + subpopulation during the later stages of treatment, raising speculation about the potential involvement of these lymphocyte expansions in mechanisms related to antitumor immunity.

P2, N=120, Active, not recruiting, Zhejiang DTRM Biopharma | Recruiting --> Active, not recruiting

Persons with myeloma were randomized to receive an anti-TIGIT (T cell immunoreceptor) or anti-LAG3 (lymphocyte activation gene) antibody followed by combination with pomalidomide and dexamethasone ( NCT04150965 ). Anti-TIGIT responders had higher CD226 expression, natural killer cell activation and lower CD112 expression. These data demonstrate the clinical activity of TIGIT-LAG3 blockade and identify pathway-specific response correlates in myeloma.

P1/2, N=50, Active, not recruiting, MediciNova | Trial completion date: Jun 2024 --> Dec 2024

P2, N=36, Completed, MediciNova | Active, not recruiting --> Completed | Trial completion date: Dec 2023 --> Aug 2024

P2, N=120, Recruiting, Zhejiang DTRM Biopharma | Trial completion date: Mar 2024 --> Dec 2024 | Trial primary completion date: Mar 2024 --> Dec 2024

P2, N=34, Not yet recruiting, Center Eugene Marquis

Pomalidomide, which degrades IKZF1 and IKZF3, induced IFN-γ overproduction in human Treg cells. Mechanistically, the Foxp3-Ikzf1-Ikzf3 complex competed with epigenetic co-activators, such as p300, for binding to target gene loci via chromatin remodeling. Therefore, the Ikzf1 association with Foxp3 is essential for the gene-repressive function of Foxp3 and could be exploited to treat autoimmune disease and cancer.

P2, N=29, Recruiting, City of Hope Medical Center | Trial completion date: Jun 2024 --> Feb 2027 | Trial primary completion date: Jun 2024 --> Feb 2027

P2, N=120, Recruiting, VA Office of Research and Development | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Jun 2024 --> Jun 2025

P1/2, N=101, Active, not recruiting, University of Chicago | Recruiting --> Active, not recruiting | Phase classification: P1b/2 --> P1/2

P1/2, N=18, Completed, Kolon Life Science | Active, not recruiting --> Completed | Trial primary completion date: Oct 2022 --> Oct 2023

P2, N=120, Recruiting, GERCOR - Multidisciplinary Oncology Cooperative Group | Not yet recruiting --> Recruiting | Initiation date: Mar 2024 --> Jul 2024

Enzyme inhibition experiments led to the discovery of the compound 10d, which exhibited moderate inhibitory potency (IC50 of 5.9 ± 0.7 μM), but unfortunately demonstrated no activity in D-DT degradation experiments. In conclusion, this study offers valuable insight into the SAR of D-DT inhibition, paving the way for the development of novel molecules as tools to study D-DT functions in tumor proliferation and, ultimately, new therapeutics for cancer treatment.

Thus, while MSCs support the presence of these immature cell populations, they simultaneously inhibit their maturation. This finding provides novel mechanistic insights into lenalidomide- and pomalidomide-induced cytopenia, and could guide therapeutic strategies for its mitigation.

Furthermore, we develop a novel RALY protein degrader based on peptide proteolysis-targeting chimeras, named RALY-PROTAC, which we chemically synthesize by linking a RALY-targeting peptide with the E3 ubiquitin ligase recruitment ligand pomalidomide. In conclusion, our findings demonstrate a novel mechanism by which O-GlcNAcylation/RALY/USP22 mRNA axis aggravates HCC cells proliferation. RALY-PROTACs as degraders of the RALY protein exhibit potential as therapeutic drugs for RALY-overexpressing HCC.

P2, N=40, Active, not recruiting, Fondazione IRCCS Policlinico San Matteo di Pavia | Recruiting --> Active, not recruiting | Trial completion date: Mar 2024 --> Jan 2025 | Trial primary completion date: Mar 2024 --> Nov 2024

P=N/A, N=5, Active, not recruiting, Kolon Life Science | Enrolling by invitation --> Active, not recruiting

P2, N=23, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Dec 2025

P1, N=8, Active, not recruiting, Exeliom Biosciences | Recruiting --> Active, not recruiting | N=67 --> 8 | Trial completion date: Oct 2025 --> Oct 2024 | Trial primary completion date: Oct 2025 --> Oct 2024

P2, N=21, Recruiting, Weill Medical College of Cornell University | Trial completion date: Dec 2028 --> Dec 2029 | Trial primary completion date: Dec 2024 --> Dec 2025

P2, N=40, Recruiting, Weill Medical College of Cornell University | Trial completion date: Jan 2034 --> Sep 2030 | Trial primary completion date: Sep 2024 --> Sep 2025

In our study, we developed a PROTAC-mimetic probe dPA by combining PACMA31 (PA) analogs with cereblon-directed pomalidomide...Our findings highlight a novel strategy for PDIA1 inhibition via targeted degradation, offering promising prospects in cancer therapeutics. This approach may overcome limitations of conventional inhibitors, presenting new avenues for advancing anti-cancer interventions.

P1/2, N=21, Not yet recruiting, University Hospital, Lille

P1/2, N=56, Recruiting, Hospices Civils de Lyon | Not yet recruiting --> Recruiting

P2, N=210, Recruiting, Shaperon | Not yet recruiting --> Recruiting

P=N/A, N=100, Recruiting, Nanjing University School of Medicine

P2, N=53, Completed, Celgene | Trial primary completion date: Nov 2018 --> Sep 2023

P2/3, N=230, Recruiting, MediciNova | Trial completion date: Dec 2024 --> Dec 2026 | Trial primary completion date: Dec 2024 --> Dec 2025

P2/3, N=230, Recruiting, MediciNova | Trial primary completion date: Dec 2023 --> Dec 2024

P1/2, N=50, Active, not recruiting, MediciNova | Phase classification: P1b/2a --> P1/2

Multi-agent regimens incorporating immunomodulatory (IMiD®) agents such as thalidomide, lenalidomide, and pomalidomide have become the preferred standard of care for the treatment of patients with multiple myeloma (MM), resulting in improved survival outcomes. Here, we discuss AEs associated with pomalidomide and present five clinically relevant hypothetical case studies in patients with RRMM to provide scenario-driven guidance regarding treatment selection and AE prevention and management in the clinical setting. Lastly, as new treatment approaches continue to be explored in MM, we also discuss novel cereblon E3 ligase modulator (CELMoD™) agents including iberdomide (CC-220) and mezigdomide (CC-92480).

P1/2, N=56, Not yet recruiting, Hospices Civils de Lyon

P2, N=29, Active, not recruiting, Emory University | Trial completion date: Aug 2024 --> Mar 2026 | Trial primary completion date: Jul 2024 --> Mar 2025

Based on the cocultures, adding pomalidomide significantly promoted IFN-γ and TNF-α secretion (P < .05). Based on the above clinical and in vitro studies demonstrating the co-administration of pomalidomide with CAR-T cell treatment demonstrated favorable tolerability and therapeutic effectiveness in RRMM or B-cell leukemia/lymphoma.

P1/2, N=56, Active, not recruiting, Cristina Gasparetto | Trial completion date: Jan 2023 --> Jan 2025

P2, N=17, Active, not recruiting, Mayo Clinic | Recruiting --> Active, not recruiting | N=190 --> 17

P2, N=54, Active, not recruiting, Amgen | Trial completion date: Dec 2025 --> Oct 2024

P2, N=43, Recruiting, Shanxi Bethune Hospital