Molecular Mechanisms of Cereblon-Interacting Small Molecules in Multiple Myeloma Therapy

Costacurta, Matteo; He, Jackson; Thompson, Phillip E.; Shortt, Jake

doi:10.3390/jpm11111185

Cited by 15 publications

(6 citation statements)

References 117 publications

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“…Multiple myeloma is an incurable plasma cell malignancy that is sensitive to both epigenetically targeted [ 22 ] and immunomodulatory therapies [ 23 ]. It is also hallmarked by significant skeletal complications, including bone lysis and osteoporosis [ 24 ].…”

Section: Introductionmentioning

confidence: 99%

A phase 1 clinical trial of the repurposable acetyllysine mimetic, n-methyl-2-pyrrolidone (NMP), in relapsed or refractory multiple myeloma

et al. 2023

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Background N-methyl-2-pyrrolidone (NMP) is an epigenetically active chemical fragment and organic solvent with numerous applications including use as a drug-delivery vehicle. Previously considered biologically inert, NMP demonstrates immunomodulatory and anti-myeloma properties that are partly explained by acetyllysine mimetic properties and non-specific bromodomain inhibition. We therefore evaluated orally administered NMP in a phase 1 dose-escalation trial to establish its maximum tolerated dose (MTD) in patients with relapsed/refractory multiple myeloma (RR–MM). Secondary endpoints were safety, pharmacokinetics (PK), overall response rate and immunological biomarkers of activity. Results Thirteen patients received NMP at starting doses between 50 and 400 mg daily. Intra-patient dose escalation occurred in five patients, with one attaining the ceiling protocolised dose of 1 g daily. Median number of monthly cycles commenced was three (range 1–20). Grade 3–4 adverse events (AEs) were reported in seven (54%; 95% CI 25–81%) patients. Most common AEs (> 30% of patients) of any grade were nausea and musculoskeletal pain. The only dose limiting toxicity (DLT) was diarrhoea in a patient receiving 200 mg NMP (overall DLT rate 8%; 95% CI 0–36%). Hence, the MTD was not defined. Median progression-free and overall survival were 57 (range 29–539) days and 33 (95% CI 9.7– > 44) months, respectively. The best response of stable disease (SD) was achieved in nine patients (69%; 95% CI 39–91%). PK analysis demonstrated proportional dose–concentrations up to 400 mg daily, with a more linear relationship above 500 mg. Maximum plasma concentrations (Cmax) of 16.7 mg/L at the 800 mg dose were below those predicted to inhibit BET-bromodomains. Peripheral blood immune-profiling demonstrated maintenance of natural killer (NK) cells, and a gene expression signature suggestive of enhanced T, B and NK cell functions; a subject with prolonged exposure manifested sustained recovery of B and NK cells at 12 months. Conclusions NMP demonstrated potential disease stabilising and immunomodulatory activity at sub-BET inhibitory plasma concentrations and was well tolerated in RR–MM; an MTD was not determined up to a maximum dose of 1 g daily. Further dose-finding studies are required to optimise NMP dosing strategies for therapeutic intervention.

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Section: Introductionmentioning

confidence: 99%

A phase 1 clinical trial of the repurposable acetyllysine mimetic, n-methyl-2-pyrrolidone (NMP), in relapsed or refractory multiple myeloma

et al. 2023

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“…Although acting on the E3 ligase-related function of CRBN appears to be the main mechanism for the anti-myeloma activity of IMiDs [ 12 , 13 ], recent reports indicate that IMiDs also act by modulating other properties of CRBN, such as chaperone function [ 14 , 15 ]. Therefore, to emphasize the broader biological activity, the next generation of IMiD is called ‘CELMoDs’ (Cereblon E3 ligase modulators).…”

Section: Introductionmentioning

confidence: 99%

CRL4CRBN E3 Ligase Complex as a Therapeutic Target in Multiple Myeloma

Barankiewicz

Salomon-Perzyński

Misiewicz-Krzemińska

et al. 2022

Cancers

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Multiple myeloma (MM) is the second most common hematological malignancy with a recurrent clinical course. The introduction of immunomodulatory drugs (IMiDs) was one of the milestones in MM therapy leading to a significant improvement in patients’ prognosis. Currently, IMiDs are the backbone of MM therapy in newly diagnosed and relapsed/refractory settings. It is now known that IMiDs exert their anti-myeloma activity mainly by binding cereblon (CRBN), the substrate receptor protein of the CRL4 E3 ubiquitin ligase (CRL4CRBN) complex. By binding CRBN, IMiDs alter its substrate specificity, leading to ubiquitination and proteasomal degradation of proteins essential for MM cell survival. Following the success of IMiDs, it is not surprising that the possibility of using the CRL4CRBN complex’s activity to treat MM is being further explored. In this review, we summarize the current state of knowledge about novel players in the MM therapeutic landscape, namely the CRBN E3 ligase modulators (CELMoDs), the next generation of IMiDs with broader biological activity. In addition, we discuss a new strategy of tailored proteolysis called proteolysis targeting chimeras (PROTACs) using the CRL4CRBN to degrade typically undruggable proteins, which may have relevance for the treatment of MM and other malignancies in the future.

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“…This Special Issue of the Journal of Personalized Medicine entitled "Targeted therapy in Leukaemia, Lymphoma and Myeloma" contains 10 publications authored by experts working in a diverse range of haematological cancers including B cell non-Hodgkin lymphoma [22][23][24][25], T-cell non-Hodgkin lymphoma [26], Multiple Myeloma [27][28][29], Chronic Lymphocytic Leukaemia [23,25,28], Acute Myeloid Leukaemia [28,30] and Acute Lymphoblastic Leukemia [31].…”

mentioning

confidence: 99%

“…These neoplasms are biologically distinct but share biological features which enable certain agents to be used across a broad range of tumours including BCL2 inhibitors in B cell non-Hodgkin lymphoma, Multiple Myeloma, Chronic Lymphocytic Leukaemia, Acute Myeloid Leukaemia [28,30]; hypomethylating agents in T cell Lymphoma and Acute Myeloid Leukaemia [26,30]; BTK inhibitors in Chronic Lymphocytic Leukaemia and B cell lymphoma [25]; Cereblon-Interacting Small Molecules in Follicular Lymphoma and Myeloma [22,27,29]; and Bispecific antibodies in B cell lymphoma and B Lymphoblastic leukaemia [24,31].…”

mentioning

confidence: 99%