The design of TO-1187 was achieved by linking our previously reported HDAC6 inhibitor, TO-317, to the cereblon (CRBN) E3 ligase ligand, pomalidomide...In vivo evaluation confirmed that TO-1187 efficiently degraded HDAC6 in mouse tissues, measured 6 h after intravenous injection. In summary, TO-1187 represents a viable candidate for advanced preclinical evaluation of HDAC6 biology.

P2, N=34, Recruiting, Center Eugene Marquis | Not yet recruiting --> Recruiting

P2, N=27, Terminated, Fondazione IRCCS Policlinico San Matteo di Pavia | N=40 --> 27 | Active, not recruiting --> Terminated; low patient enrollment rate

P2/3, N=460, Active, not recruiting, University Health Network, Toronto | Suspended --> Active, not recruiting | Trial completion date: Dec 2026 --> Mar 2025 | Trial primary completion date: May 2026 --> Mar 2025

In this study, we investigated the effects of pomalidomide, an immunomodulatory imide drug that induces the degradation of Ikaros and Aiolos, on HIV latency reversal and death of infected cells. Using CD4+ T cells from people living with HIV on suppressive antiretroviral therapy, as well as an in vitro model of productive HIV infection, we found that pomalidomide induced T cell activation and expression of stress proteins but no evidence of latency reversal or selective death of infected cells.

P2/3, N=460, Suspended, University Health Network, Toronto | N=1000 --> 460 | Recruiting --> Suspended

Previous data suggests almost one third of myeloma patients acquire mutations in the key IMiD effector cereblon by the time they are pomalidomide refractory. Dynamic modelling based on a newly generated crystal structure of the DDB1/CRBN/lenalidomide complex, with greater resolution than those published to date, helped to understand the impact of these mutations. These results have important implications for the interpretation of CRBN sequencing results from patients for future therapy decisions, particularly differentiating those who may, despite relapsing on IMiDs with CRBN mutations, have the potential to still benefit from the use of CELMoD agents.

P4, N=40, HenanCancerHospital; He'nan Cancer Hospital

P1/2, N=25, Recruiting, SUNHO（China）BioPharmaceutical CO., Ltd. | Trial completion date: Jun 2024 --> Dec 2025 | Trial primary completion date: Jun 2024 --> Nov 2025

P2, N=55, Terminated, Zhejiang DTRM Biopharma | N=120 --> 55 | Active, not recruiting --> Terminated; Despite the efforts of our dedicated team and initial progress, we were unable to secure the necessary financial resources to continue the study. We appreciate the support and participation of all involved.

Our findings revealed that the highly selective PTGES3 proteolysis is a potential therapeutic strategy for HCC, and PTGES3 degraders PTGES3-PROTACs can be developed as safe and effective drugs for HCC treatment.

P=N/A, N=0, Available, Mayo Clinic

The molecules are based on connecting a known MYC binder to a VHL ligand or pomalidomide to induce MYC degradation in various cancer cells known to express MYC...Encouraging results presented herein suggest that the presented analogs may serve as prototype structures of future therapeutic agents for the treatment of MYC-dependent tumors. MYC protein degraders can well complement the more established inhibition approaches that have been presented in the past (e.g., disruption of the MYC-MAX complex formation by small-molecule inhibitors).

P2/3, N=1000, Recruiting, University Health Network, Toronto | Trial completion date: Dec 2025 --> Dec 2026 | Trial primary completion date: May 2025 --> May 2026

P2/3, N=60, Not yet recruiting, SUNHO（China）BioPharmaceutical CO., Ltd.

P2, N=124, Active, not recruiting, University of Leeds | Trial completion date: Jun 2023 --> Jun 2025

P1/2, N=21, Recruiting, University Hospital, Lille | Not yet recruiting --> Recruiting

P1, N=8, Not yet recruiting, Xalud Therapeutics, Inc.

P1/2, N=101, Active, not recruiting, University of Chicago | Trial completion date: Nov 2024 --> Nov 2025 | Trial primary completion date: Nov 2024 --> Nov 2025

P2, N=54, Completed, Amgen | Active, not recruiting --> Completed

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