P1, N=0, Withdrawn, Philogen S.p.A. | N=32 --> 0 | Not yet recruiting --> Withdrawn

P2, N=26, Completed, AIDS Malignancy Consortium | Trial completion date: Jan 2026 --> Apr 2025 | Active, not recruiting --> Completed

In the present study, we established a modular synthetic platform to systematically generate a set of PROTAC degrader candidates consisting of the CK1δ-specific inhibitor scaffold, alkyl and PEG linker motifs with various lengths, and Cereblon (CRBN)-engaging pomalidomide and thalidomide derivatives as E3 ligase binders. The most potent PROTAC P1d inhibits the phosphorylation of downstream substrates through CK1δ/ε degradation. We establish the requirement of CUL4ACRBN and the proteasome for the P1d-mediated degradation of CK1δ/ε.

Mechanistically, TPM3-TRKA degradation by compound 9 was dependent on CRBN-mediated polyubiquitination and proteasomal degradation; accordingly, it was hindered by inhibitors of the proteasome (MG132) or Cullins (MLN4924), by dominant negative Cullin 4A mutant, and by free pomalidomide. Finally, a compound 9 derivative, compound 20, induced in vivo degradation of TMP3-TRKA in KM12 cells mouse xenografts. In conclusion, our study indicated that PROTAC-mediated degradation is an efficient strategy to intercept RET and TRKA oncogenic signaling.

P1, N=42, Not yet recruiting, Philogen S.p.A.

Given the immune-enhancing effects and excellent safety profile, pomalidomide should be further investigated as an immune-enhancing strategy for an HIV cure.

P=N/A, N=46, Recruiting, The First Affiliated Hospital of Zhejiang University School of Medicine; The First Affiliated Hospital of Zhejiang University School of Medicine

P2, N=15, Active, not recruiting, Weill Medical College of Cornell University | Trial completion date: Sep 2027 --> Jan 2028 | Trial primary completion date: Sep 2025 --> Jan 2026

PROTAC MA203 contains the type I kinase inhibitor rabusertib, which preferentially inhibits activated CHK1, and the cereblon (CRBN) ligand pomalidomide. Genetic CHK1 elimination confirms that such newly recognized functions of CHK1 rely on functions beyond its well-known catalytic activity. Thus, kinase-independent functions of CHK1 can be exploited with innovative pharmacological agents.

Weekly selinexor in combination with pomalidomide or carfilzomib in particular showed efficacy in difficult-to-treat, multiclass relapsed/refractory MM, including MM refractory to prior BCMA-directed therapies. In a rapidly evolving field of previously treated MM, lowering of selinexor dose and frequency into weekly regimens showed a more feasible and tolerable treatment with continued efficacy when compared to twice-weekly schedules, paving the path for effective management of multiclass refractory MM, including patients with very advanced disease.

THP exerted the analgesic role in BCP might be through inactivating the TNF-α/uPA/PAR2/TRPV1 pathway in DRG. It may be an effective drug for relieving BCP in patients.

P2, N=9, Active, not recruiting, Weill Medical College of Cornell University | Trial completion date: Aug 2027 --> Dec 2027 | Trial primary completion date: Aug 2025 --> Dec 2025