Breakthroughs in treatment for hematological malignancies: latest updates on molecular glue, PROTACs and RNA degraders from ASH 2024

Abstract

Degrader therapies have garnered significant attention for their innovative approach to targeting and eliminating malignancy-associated proteins, holding promise for improving outcomes for patients with relapsed or refractory (R/R) hematological malignancies, especially in cases of leukemia, non-Hodgkin lymphoma, and multiple myeloma. Currently, the main categories developed based on degraders include molecular glue (such as Cemsidomide, NX-5948), PROTACs (such as BGB-16673, AC-676, KT-333 ), and RNA degraders (such as SKY-1214). This correspondence summarizes the preclinical and clinical updates on degrader therapies presented at the ASH 2024 annual meeting.

To the editor

Degraders are novel therapeutic agents designed to target specific proteins for degradation within cells, utilizing the cell’s own protein disposal system (not only the ubiquitin-proteasome system but also the autophagy-lysosome system). The development of degraders is an active area of research, with numerous candidates currently undergoing preclinical studies and clinical trials. This report summarizes the latest updates at the ASH 2024 annual meeting on the research of degraders.

Preclinical studies

The preclinical studies of degraders are summarized in Table 1. The landscape is predominantly shaped by molecular glue (MG) and Proteolysis Targeting Chimeras (PROTAC) modalities, with a notable emergence of new modalities such as the DAC (Degrader-Antibody Conjugate) represented by HDZ-C123A [1] and the mRNA degrader exemplified by SKY-1214 ². The majority of these compounds utilize E3 Ligase Dependent mechanisms for degradation. Notably, SKY-1214 stands out as an mRNA degrader that targets FANCL and FANCI [2]. Current preclinical research is evaluating innovative targets, with IRF4, CBP/p300, MALT1, BCR::ABL1, KAT2A/B, IRAK1/4 and others being identified as promising in broadening treatment options for various hematological disorders (Table 1). In particular, degradation may hold promise for a myriad of lymphocytic malignancies, including Multiple Myeloma (MM), Chronic Lymphocytic Leukemia (CLL), Acute Lymphoblastic Leukemia (ALL), and Non-Hodgkin Lymphoma (NHL).

In addition to the first-in-class degrader compounds presented at ASH 2024, recent research advancements on previously reported degrader compounds were also highlighted, as detailed in the supplementary materials Table S1.

Table 1 Preclinical studies of degraders presented at ASH 2024

Clinical trials

Table 2 provides a detailed overview of the results from clinical trials of degraders presented at the ASH 2024 conference. BGB-16,673 targets BTK (Bruton’s Tyrosine Kinase) and is undergoing Phase 1/2 clinical trials. It is being tested for R/R waldenström macroglobulinemia (WM) with 22 participants (NCT05006716) and for R/R CLL/small lymphocytic lymphoma (SLL) with 49 participants. BGB-16,673 demonstrated an impressive overall response rate (ORR) of 90% in patients with R/R WM [3] and a 78% ORR in those with R/R CLL/SLL [4]. NX-5948 also targets BTK and is in phase 1a/b trials for R/R B-cell malignancies, showed a 76.7% ORR in patients with R/R CLL (NCT06691828) [5]. AC676, another PROTAC targeting BTK, is in phase 1 clinical trials for R/R B-cell malignancies(NCT05780034) [6]. Cemsidomide, which targets IKZF1/3 ( Ikaros Family Zinc Finger Proteins 1 and 3), is in phase 1/2 trials for NHL with 20 patients and for R/R MM with 32 patients, achieved a 25% ORR in NHL patients [7], many of which being T-cell lymphomas, and a 22% ORR in R/R MM (NCT04756726) [8]. KT-333, a PROTAC that targets STAT3 with a VHL Dependent mechanism, is in phase 1a/1b trials for a broad range of conditions including R/R B- and T-cell lymphomas, classical Hodgkin lymphoma (cHL), solid tumors (ST), and large granular lymphocytic-leukemia/T-cell prolymphocytic leukemia (LGL-L/T-PLL), exhibiting a 31.4% ORR with 51 patients enrolled (NCT05225584) [9]. Preliminary data from these phase 1 trials suggest that these degraders exhibit favorable safety and tolerability profiles, along with promising clinical activity.

Table 2 Outcomes of clinical trials of degraders presented at ASH 2024

These updates from ASH 2024 underscore the dynamic progress in the field of targeted protein degradation, with a focus on innovative approaches to combat hematological diseases and other malignancies. The innovative aspects of these degraders, such as dual targeting, immunomodulatory activity, and combination therapies, highlight the potential for more effective and personalized treatment options in the future.