thalidomide

P2, N=30, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Feb 2026 --> Feb 2027 | Trial primary completion date: Feb 2026 --> Feb 2027

Mechanistically, the CRL4ACRBN E3 complex ubiquitinates KEAP1 at K84 and K312, driving KEAP1 degradation. CRBN inhibitor thalidomide and IKE combination treatment results in markedly retarded tumor progression. Our study reveals a crucial pro-ferroptotic role for TrxR1 and nominates it as a potential biomarker for guiding future ferroptosis-inducing therapies in select cancers.

P2, N=232, Recruiting, Medical University of Vienna | N=100 --> 232

P4, N=55, Completed, Institute of Hematology & Blood Diseases Hospital, China | Unknown status --> Completed

P4, N=44, Completed, Institute of Hematology & Blood Diseases Hospital, China | Unknown status --> Completed

P3, N=177, Active, not recruiting, University of Arkansas | Trial completion date: Aug 2026 --> Aug 2027 | Trial primary completion date: Aug 2026 --> Aug 2027

P3, N=300, Active, not recruiting, Australasian Leukaemia and Lymphoma Group (ALLG) | Recruiting --> Active, not recruiting

Cereblon (CRBN) is the target of thalidomide derivatives1 that achieve therapeutic efficacy against some haematologic neoplasias2-4 by recruiting neosubstrates for degradation5-7...Structural investigations provide a mechanistic basis for the effects of the allosteric ligand by shifting the conformational distribution of CRBNopen to a novel CRBNint and increasing the CRBNclosed state. The discovery of a cryptic allosteric binding site on CRBN that alters the functional effects of orthosteric ligands opens new directions with broad implications for improving the selectivity and efficacy of CRBN therapeutics.

We design and synthesize heterobifunctional molecules that consist of flufenamic acid analogs that bind to the allosteric TEAD lipid pocket, a long and flexible linker, and thalidomide to engage E3 ubiquitin ligase component cereblon...Methyl ester analogs of these compounds led to substantial proteasomal degradation of the TEAD•YAP/TAZ complex in cancer cells. This work provides a strategy for depletion of nuclear YAP and TAZ and for exploration of their TEAD-dependent and TEAD-independent activities in vivo .

P=N/A, N=545, Completed, Shanghai Zhongshan Hospital

The pomalidomide/thalidomide-based series (BP1-BP5) exhibited strong antiproliferative activity against leukemia and multiple myeloma cells, accompanied by degradation of CRBN neosubstrates. The hit compounds from both series, BP1 (DC50, 24 h = 20 nM, Dmax, 24 h = 99%) and BP6 (DC50, 24 h = 81 nM, Dmax, 24 h = 93%), demonstrated highly efficient and selective HDAC8 degradation. Pretreatment with BP6 enhanced the tumor suppressor p53 stability, thereby significantly increasing the sensitivity of leukemia cells to the MDM2 antagonist idasanutlin than PCI-34051, highlighting its unique potential for combinatorial therapy without impacting neosubstrates.

P2/3, N=222, Not yet recruiting, Shanghai Zhongshan Hospital