Furthermore, with the deep penetration of two-photon excitation, Ru-Poma achieved drug-resistant circumvention in a 3D tumor cell model. Thus, we describe the first sample of the CRBN-targeting Ru(II) complex active in PDT.

P1, N=36, Recruiting, Celgene | Not yet recruiting --> Recruiting

P1/2, N=424, Active, not recruiting, Celgene | Recruiting --> Active, not recruiting

However, thalidomide and its approved derivatives remain plagued by several shortcomings, such as structural instability and poor solubility. Herein, we present a review of strategies for mitigating these shortcomings and highlight contemporary drug discovery approaches that have generated novel thalidomide analogs with enhanced efficacy as cereblon effectors and/or anticancer agents.

Altogether, compound 1 is a valuable chemical biology tool to study the role of PRC1 in cancer. Importantly, we show that CRBN can be utilized to develop bridged PROTACs, expanding the bridged PROTAC technology for degrading undruggable proteins.

P1, N=36, Not yet recruiting, Celgene

P3, N=850, Not yet recruiting, Celgene

The vast majority of current cereblon (CRBN) ligands is based on the thalidomide scaffold, relying on glutarimide as the core binding moiety...In this new orientation it forms additional hydrophobic interactions and is not available for direct interactions with the canonical neo-substrates. We therefore propose this chemotype as an attractive building block for the design of PROTACs.

P1, N=30, Recruiting, Kangpu Biopharmaceuticals, Ltd. | Trial completion date: May 2024 --> May 2025 | Trial primary completion date: Jan 2024 --> Oct 2024

Preclinical studies of mezigdomide have demonstrated its anti-proliferative and apoptotic effects in MM, along with its immune-stimulatory effects and its synergistic activity with other antimyeloma agents, including in lenalidomide-/pomalidomide-resistant MM cell lines and mouse xenograft models. Early-phase clinical trial data indicate notable activity in heavily pretreated patients with RRMM, including those with triple-class-refractory disease, together with a tolerable and manageable safety profile. This review summarizes current preclinical and clinical findings with mezigdomide and its potential future roles in the treatment of MM.

P1, N=32, Not yet recruiting, Celgene

P1/2, N=156, Recruiting, Celgene | Not yet recruiting --> Recruiting | Trial primary completion date: Dec 2027 --> Feb 2032

P2, N=65, Not yet recruiting, The Lymphoma Academic Research Organisation

P1, N=15, Recruiting, City of Hope Medical Center | Initiation date: Dec 2023 --> Mar 2024

P1/2, N=220, Recruiting, Bristol-Myers Squibb | Phase classification: P1b/2a --> P1/2

Lenalidomide (LEN; a second-generation immunomodulatory drug [IMiD]) has been employed as an additional therapeutic option for ATL since 2017, but its mechanism of action has not been fully proven, and recent studies reported emerging concerns about the development of second primary malignancies in patients treated with long-term IMiD therapy. Finally, a novel cereblon modulator (CELMoD), iberdomide (IBE), exhibited a broader and deeper spectrum of growth suppression to ATL cells with efficient IKZF2 degradation, which was not observed in other IMiD treatments. Based on these findings, our study strongly supports the novel therapeutic advantages of IBE against aggressive and relapsed ATL.

P1, N=32, Completed, Bristol-Myers Squibb | Recruiting --> Completed

Cereblon-targeting degraders, including immunomodulatory imide drugs lenalidomide and pomalidomide alongside cereblon E3 ligase modulators like iberdomide and mezigdomide, have demonstrated significant anti-myeloma effects...Despite their evident efficacy, approximately 5% to 10% of MM patients exhibit primary resistance to lenalidomide, and resistance commonly develops over time. Understanding the intricate mechanisms of action and resistance to this drug class becomes imperative for refining and advancing novel therapeutic combinations.

P1, N=18, Recruiting, Nathan Denlinger | Not yet recruiting --> Recruiting

P1, N=174, Terminated, Celgene | Active, not recruiting --> Terminated; Replaced with another clinical trial.

P1, N=18, Not yet recruiting, Nathan Denlinger

In two KRAS G12C xenograft models, BTX-6654 degraded SOS1 in a dose-dependent manner correlating with tumor growth inhibition, additionally exhibiting synergy with KRAS and MEK inhibitors. Altogether, BTX-6654 provided preclinical proof of concept for single-agent and combination use of bifunctional SOS1 degraders in KRAS-driven cancers.

P1/2, N=424, Recruiting, Celgene | Trial completion date: Jul 2026 --> Nov 2026 | Trial primary completion date: Nov 2023 --> Nov 2026

P1, N=12, Active, not recruiting, Bristol-Myers Squibb | Recruiting --> Active, not recruiting

Importantly, tumor xenograft research clearly showed W13's promising antitumor activity against human lung cancer. Taken together, the discovery of W13 demonstrated the practicality and feasibility of PROTAC targeting tubulin, hence establishing a potential therapeutic approach for treating NSCLC caused by the overexpression of β3-tubulin.

These results collectively suggest that THBS-1 represents an endogenous substrate of cereblon. This pairing is disrupted by IMiDs, and the aberrant accumulation of THBS-1 plays an important role in the pathogenesis of IMiDs-induced thromboembolism.

P1, N=174, Recruiting, Celgene | Phase classification: P1b --> P1

We have previously identified IKZF1/IKAROS as a target in KMT2A-r AML and shown in preclinical models that IKAROS protein degradation with lenalidomide or iberdomide has modest single-agent activity yet can synergize with Menin inhibitors. The combination of mezigdomide with the Menin inhibitor VTP-50469 increased survival and prevented and overcame MEN1 mutations that mediate resistance in patients receiving Menin inhibitor monotherapy. These results support prioritization of mezigdomide for early phase clinical trials in KMT2A-r and NPM1c AML, either as a single-agent or in combination with Menin inhibitors.

P1, N=271, Completed, Celgene | Active, not recruiting --> Completed | Phase classification: P1a/1b --> P1

P1/2, N=156, Not yet recruiting, Celgene

Similar synergistic effects were found when combining GOLCA with JQ1, another tool compound BET inhibitor, confirming BET inhibition potentiates the anti-DLBCL effects of the CELMoD agent. BET inhibition potentiates anti-proliferative effects of GOLCA in DLBCL cells through synergistic induction of p21 and inhibition of E2F signaling. The synergetic effects of BMS-986158 and GOLCA suggest potential clinical benefits of combining lower doses of single agents to achieve better efficacy with reduced risk of adverse effects.

Introduction: CRBN mediated degradation of Ikaros by Pomalidomide (Pom) and Mezigdomide (Mezi) results in robust antiproliferative activity against myeloma cells, with concomitant activation of immune cells such as T and NK cells...Mezi treated animals who were co-administered dexamethasone demonstrated partially enhanced early progenitor populations compared to single agent Mezi... These studies delineate previously unreported effects of CELMoDs on a multifaceted continuum of myelopoiesis. These insights will help rationally design dose and schedule considerations for CELMoD treatment regimens alone, or in combination with other therapeutic agents to alleviate CELMoD induced neutropenia.

P1/2, N=85, Recruiting, Bristol-Myers Squibb | Not yet recruiting --> Recruiting

P1, N=15, Recruiting, City of Hope Medical Center | Trial completion date: Jul 2025 --> Mar 2026 | Trial primary completion date: Jul 2025 --> Mar 2026

P1, N=174, Active, not recruiting, Celgene | Phase classification: P1b --> P1 | Trial completion date: Oct 2023 --> Jan 2024 | Trial primary completion date: Oct 2023 --> Jan 2024

P1/2, N=34, Recruiting, Kathleen Dorritie | Not yet recruiting --> Recruiting

The next-generation cereblon-targeting agent mezigdomide shows early signs of clinical efficacy in patients with heavily pretreated multiple myeloma, highlighting the potential of rational drug design to improve the potency of immunomodulatory therapies that function as molecular glues.

Golcadomide oral therapy combined with rituximab showed promising efficacy in heavily pretreated patients with R/R DLBCL, including 1 durable response over 300 days. Golcadomide can be safely combined with rituximab, and the combination showed a safety profile similar to that previously reported for golcadomide monotherapy.

These results also suggest that MEZI may be useful in combination with other agents for increasing immune activation and reducing immune exhaustion. Further analyses comparing the effect of different CELMoDs on the BM TME are ongoing.

Introduction Up to 40% of pts with diffuse large B-cell lymphoma (DLBCL) relapse after first-line chemo-immunotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP)...CC-220-DLBCL-001 (NCT04884035) is an ongoing open-label, multicenter, dose escalation and expansion trial to assess safety and preliminary efficacy of CELMoD agents + R-CHOP for untreated a-BCL...Efficacy results and substantial ctDNA decrease indicate robust clinical activity in frontline DLBCL, with a high CMR rate at EoT, particularly among patients treated at DL1. Study support Bristol Myers Squibb.

Following concentration/duration optimisation, cell lines were treated with EZH2i (Tazemetostat) 0.25-1µM or DMSO control for 5 days alone, and then in combination with IMiD (Lenalidomide, Len, 0-20 µM, Pomalidomide, Pom, 0-8 µM) or CELMoD (Iberdomide, CC-220, 0-2 µM and Mezigdomide, CC-92480, 0-0.1uM) for a further 5 days. Conclusions Our results suggest that combining EZH2i with IMiDs/CELMoDs can overcome resistance to these agents in MM cell line models, with synergy that is CRBN-dependent. By examining the key components of the CRBN pathway we identified that EZH2i reduced H3K27me3 and increased Ikaros and Aiolos association at the IRF4 promoter, suggesting a possible re-coupling of Ikaros/Aiolos to IRF4 expression, which may be responsible for reinstating IMiD/CELMoD activity, driving the synergistic effect seen.

Intravenous (IV; 16 mg/kg) or subcutaneous (1800 mg) DARA was given weekly (C1–2), then biweekly (C3–6), and monthly (≥ C7) for subcohorts B1 and B3, and weekly (C1–3) then on D1 of each 21-D (C4–8) or 28-D (≥ C9) cycle for subcohort B2; with weekly oral/IV DEX (40 mg; 20 mg > 75 y or body mass index < 18.5 kg/m2). MeziDd showed promising efficacy and a manageable safety profile in pts with RRMM and 2–4 prior lines of therapy, as did MeziEd in pts with prior anti-CD38 mAb therapy. The immune activity of MEZI was consistent with previous preclinical reports. Improved safety and efficacy may be achieved by schedule and dose adjustments.