AML-147 C-MYC Targeting by Degradation: Novel Dual c-Myc/GSPT1 Degrader GT19715 Exerts Profound Cell Kill In Vitro and In Vivo in Acute Myeloid Leukemia and Lymphomas

Nishida, Yoshihiro; Scruggs, Darah A; Ayoub, Edward; Patsilevas, Tallie; Ruvolo, Vivian; Mak, Po Yee; Carter, Bing Z.; Boettcher, Steffen; Maiti, Abhishek; Zhou, Qing; Yang, Zhaohui; Yan, Hongping; Ma, Liandong; Andreeff, Michael

doi:10.1016/s2152-2650(22)01230-7

Cited by 5 publications

(5 citation statements)

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“…Compound 54 exhibited similar chemical properties to other CRBN modulators, and proteomic analysis showed degradation of translation termination factor GSPT1. In fact, in xenograft models of HL‐60 cells, compound 54 effectively degraded GSPT1 and completely degraded c‐Myc, and suppressed tumor progression at a minimal dose of 0.3 mg/kg/bid 131 . At a dosage of 6 mg/kg, Compound 54 did not exhibit any impact on normal myeloid lineages in rats.…”

Section: Gspt1 Mgsmentioning

confidence: 96%

“…The results showed that 54 could effectively degrade oncoprotein c‐Myc in HL‐60 cells (DC 50 = 1.5 nM). c‐Myc was effectively pulled down by biotinylated 54 in a cell‐free, in vitro affinity purification assay and the proteasome inhibitor ixazomib could completely block the degradation of c‐Myc 131 . Compound 53 demonstrated a significantly lower IC 50 of 1.8 nM against HL‐60 cells compared to the IC 50 of 40.2 nM observed in normal myeloid progenitors during CFU assay, indicating the existence of a therapeutic window.…”

Section: Gspt1 Mgsmentioning

confidence: 98%

“…GT19715 : In October 2022, a novel c‐Myc/GSPT1 dual‐target degrader, GT19715 ( 53 ), independently developed by Kintor Pharmaceuticals, showed good efficacy against AML and lymphomas, 131 but no structure and patent have been reported. c‐Myc is an oncogenic transcription factor that serves a major function in tumor genesis, cancer cell survival, proliferation and immune escape 132 .…”

Section: Gspt1 Mgsmentioning

confidence: 99%

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Development and therapeutic potential of GSPT1 molecular glue degraders: A medicinal chemistry perspective

Chang,

Qu,

et al. 2024

Medicinal Research Reviews

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Unprecedented therapeutic targeting of previously undruggable proteins has now been achieved by molecular‐glue‐mediated proximity‐induced degradation. As a small GTPase, G1 to S phase transition 1 (GSPT1) interacts with eRF1, the translation termination factor, to facilitate the process of translation termination. Studied demonstrated that GSPT1 plays a vital role in the acute myeloid leukemia (AML) and MYC‐driven lung cancer. Thus, molecular glue (MG) degraders targeting GSPT1 is a novel and promising approach for treating AML and MYC‐driven cancers. In this Perspective, we briefly summarize the structural and functional aspects of GSPT1, highlighting the latest advances and challenges in MG degraders, as well as some representative patents. The structure‐activity relationships, mechanism of action and pharmacokinetic features of MG degraders are emphasized to provide a comprehensive compendium on the rational design of GSPT1 MG degraders. We hope to provide an updated overview, and design guide for strategies targeting GSPT1 for the treatment of cancer.

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Section: Gspt1 Mgsmentioning

confidence: 96%

Section: Gspt1 Mgsmentioning

confidence: 98%

Section: Gspt1 Mgsmentioning

confidence: 99%

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Development and therapeutic potential of GSPT1 molecular glue degraders: A medicinal chemistry perspective

Chang,

Qu,

et al. 2024

Medicinal Research Reviews

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“…A second GSPT1 degrader (ORM‐5029) is also in phase I investigation for patients with HER2‐expressing advanced solid tumours [72]. A dual degrader of c‐MYC/GSPT1 (GT19715) has been described with preclinical evidence of efficacy in leukaemia and lymphoma settings [73].…”

Section: Thalidomide Analogue Neo‐substrates As Cancer Drug Targetsmentioning

confidence: 99%

The emerging role of targeted protein degradation to treat and study cancer

Brodermann,

Henderson,

Sellar

2024

The Journal of Pathology

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The evolution of cancer treatment has provided increasingly targeted strategies both in the upfront and relapsed disease settings. Small‐molecule inhibitors and immunotherapy have risen to prominence with chimeric antigen receptor T‐cells, checkpoint inhibitors, kinase inhibitors, and monoclonal antibody therapies being deployed across a range of solid organ and haematological malignancies. However, novel approaches are required to target transcription factors and oncogenic fusion proteins that are central to cancer biology and have generally eluded successful drug development. Thalidomide analogues causing protein degradation have been a cornerstone of treatment in multiple myeloma, but a lack of in‐depth mechanistic understanding initially limited progress in the field. When the protein cereblon (CRBN) was found to mediate thalidomide analogues' action and CRBN's neo‐targets were identified, existing and novel drug development accelerated, with applications outside multiple myeloma, including non‐Hodgkin's lymphoma, myelodysplastic syndrome, and acute leukaemias. Critically, transcription factors were the first canonical targets described. In addition to broadening the application of protein‐degrading drugs, resistance mechanisms are being overcome and targeted protein degradation is widening the scope of druggable proteins against which existing approaches have been ineffective. Examples of targeted protein degraders include molecular glues and proteolysis targeting chimeras (PROTACs): heterobifunctional molecules that bind to proteins of interest and cause proximity‐induced ubiquitination and proteasomal degradation via a linked E3 ligase. Twenty years since their inception, PROTACs have begun progressing through clinical trials, with early success in targeting the oestrogen receptor and androgen receptor in breast and prostate cancer respectively. This review explores important developments in targeted protein degradation to both treat and study cancer. It also considers the potential advantages and challenges in the translational aspects of developing new treatments. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

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“…Furthermore, the results of recent animal experiments suggest that the adverse side effects induced by the use of Omomyc are mild and reversible, and the therapeutic effect is improved in combination with paclitaxel 94 . Recently, GT19715, a novel dual C-MYC/GSPT1 degrader, was reported to effectively degrade C-MYC protein both in vivo and in vitro and to inhibit tumor growth at low doses in Acute Myeloid Leukemia and Lymphomas 100 . Although no therapies targeting MYC have been approved for clinical use, research conducted over the past 20 years has provided a solid foundation for the study of MYC-targeted inhibitors.…”

Section: Undruggable Targets In Cancermentioning

confidence: 99%

Emerging Pharmacotherapeutic Strategies to Overcome Undruggable Proteins in Cancer

Lu¹,

Yang²,

Zhu³

et al. 2023

Int. J. Biol. Sci.

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Targeted therapies in cancer treatment can improve in vivo efficacy and reduce adverse effects by altering the tissue exposure of specific biomolecules. However, there are still large number of target proteins in cancer are still undruggable, owing to the following factors including (1) lack of ligand-binding pockets, (2) function based on protein-protein interactions (PPIs), (3) the highly specific conserved active sites among protein family members, and (4) the variability of tertiary docking structures. The current status of undruggable targets proteins such as KRAS, TP53, C-MYC, PTP, are carefully introduced in this review. Some novel techniques and drug designing strategies have been applicated for overcoming these undruggable proteins, and the most classic and well-known technology is proteolysis targeting chimeras (PROTACs). In this review, the novel drug development strategies including targeting protein degradation, targeting PPI, targeting intrinsically disordered regions, as well as targeting protein-DNA binding are described, and we also discuss the potential of these strategies for overcoming the undruggable targets. Besides, intelligence-assisted technologies like Alpha-Fold help us a lot to predict the protein structure, which is beneficial for drug development. The discovery of new targets and the development of drugs targeting them, especially those undruggable targets, remain a huge challenge. New drug development strategies, better extraction processes that do not disrupt protein-protein interactions, and more precise artificial intelligence technologies may provide significant assistance in overcoming these undruggable targets.

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AML-147 C-MYC Targeting by Degradation: Novel Dual c-Myc/GSPT1 Degrader GT19715 Exerts Profound Cell Kill In Vitro and In Vivo in Acute Myeloid Leukemia and Lymphomas

Cited by 5 publications

References 0 publications

Development and therapeutic potential of GSPT1 molecular glue degraders: A medicinal chemistry perspective

Development and therapeutic potential of GSPT1 molecular glue degraders: A medicinal chemistry perspective

The emerging role of targeted protein degradation to treat and study cancer

Emerging Pharmacotherapeutic Strategies to Overcome Undruggable Proteins in Cancer

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