- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, Mylotarg (gemtuzumab ozogamicin) / Pfizer, Vanflyta (quizartinib) / Daiichi Sankyo
GSPT1 degrader antibody conjugate, BLB-201, for the treatment of high-risk acute myeloid leukemia (Section 11) - Mar 17, 2026 - Abstract #AACR2026AACR_4929;
BLB-201 DAC allows selective targeting of CD123-positive AML blasts and leukemia stem cells, minimizing direct exposure of GSPT1 degrader to healthy tissues. This unique mechanism of action may improve response rates when combined with existing targeted therapies for AML patients with high-risk or relapsed/refractory disease.
- |||||||||| ORM-1153 / Orum Therap
ORM-1153: A Next-Generation CD123-Targeting Degrader Antibody Conjugate (DAC) (Section 17) - Mar 17, 2026 - Abstract #AACR2026AACR_4692;
These results highlight how molecular engineering of both the antibody and linker can dramatically shift the balance between efficacy and tolerability for complex bioconjugates. Collectively, ORM-1153 exemplifies a rationally engineered DAC with superior pharmacologic properties, including robust potency and a broad therapeutic window, supporting advancement toward clinical introduction
- |||||||||| ORM-1153 / Orum Therap
ORM-1153: A novel CD123-targeting degrader antibody conjugate with proprietary GSPT1 degrading payload for the treatment of acute myeloid leukemia (Section 13) - Mar 17, 2026 - Abstract #AACR2026AACR_4479;
The only approved ADC for AML therapy is gemtuzumab ozogamicin (GO)...In addition, recent studies have reported that small-molecule GSPT1 degraders, such as CC-90009, exhibit potent antileukemic cytotoxicity in AML and demonstrate activity against TP53-mutant disease, one of the highest unmet needs...This in vitro activity is comparable to GO and ~3-log greater than venetoclax...We evaluated ORM-1153 in vivo MV4-11 xenograft model, and treatment with ORM-1153 demonstrated superior activity than standard of care treatment option. Our results indicate that ORM-1153 may represent a viable therapeutic agent for the treatment of AML, including in patients with TP53-mutant status who face limited options and an overall poor prognosis, and warrants further investigation in clinical trials.
- |||||||||| MRT-2359 / Monte Rosa Therap
Proteome-wide target engagement and ternary complex mapping of molecular glues using LiP-MS (Section 39) - Mar 17, 2026 - Abstract #AACR2026AACR_4087;
This live-cell format enables detection of secondary, compound-dependent protein recruitment events, including ternary complex formation with E3 ligases and other associated proteins.To evaluate LiP-MS performance in characterizing molecular glue mechanisms, we conducted global target identification experiments using two representative compounds: SR-4835, a cyclin K degrader that binds CDK12 and recruits DDB1, and MRT-2359, a GSPT1 degrader that engages CRBN. Live-cell LiP-MS experiments were performed at two time points (1 hour and 6 hours) to monitor compound-dependent conformational changes and protein recruitment dynamics associated with primary target engagement and potential ternary complex formation.Together, LiP-MS provides a comprehensive, high-resolution platform for mapping small-molecule target engagement and for characterizing dynamic protein recruitment events associated with molecular glue activity directly in the cellular environment.
- |||||||||| thalidomide / Generic mfg.
Journal: Synthesis and biological evaluation of Retro-2-based PROTACs reveal PEG-linker length and warhead impact on GSPT1 degradation. (Pubmed Central) - Mar 6, 2026
Contrary to initial assumptions, our results do not show proteasome-dependent degradation of the protein targets, but demonstrate that PEG-2 molecules can degrade the translation termination factor GSPT1 despite the normally propitious anchoring of the PEG linker at position 4 of the phthalimide ring. Furthermore, this study shows for the first time that GSPT1 degradation depends on the length of the flexible PEG chain linker.
- |||||||||| Review, Journal: GSPT1 degraders: research progress, development strategies and challenges. (Pubmed Central) - Oct 29, 2025
Currently, several selective GSPT1-degraders have entered clinical trials. This review summarized the research progress of various GSPT1 degraders with an emphasis on their design, activity studies and development strategy, aiming to provide valuable insights for the further development of GSPT1 degraders.
- |||||||||| Journal: Induction of Apoptosis and Activation of Endoplasmic Reticulum Stress by SJ6986 in Diffuse Large B-cell Lymphoma. (Pubmed Central) - Oct 1, 2025
This review summarized the research progress of various GSPT1 degraders with an emphasis on their design, activity studies and development strategy, aiming to provide valuable insights for the further development of GSPT1 degraders. This study validated the efficacy and safety of SJ6986 in treating DLBCL and discovered its role in inducing ER stress and subsequent apoptosis, offering a promising therapeutic option for DLBCL patients.
- |||||||||| Journal: Identification of potent and orally bioavailable GSPT1 molecular glue degraders. (Pubmed Central) - Sep 22, 2025
Here, we report our efforts on Structure-Activity Relationship studies around an innovative tricyclic-containing derivatives as potent and orally bioavailable GSPT1 degraders. An in vivo xenograft model study showed that one of the synthesized compounds (26) effectively suppressed NCI-N87 tumor growth, suggesting a direction in the development of novel GSPT1 degraders.
- |||||||||| Journal: Targeting of IRAK4 and GSPT1 enhances therapeutic efficacy in AML via c-Myc destabilization. (Pubmed Central) - Aug 27, 2025
These effects were validated in AML patient cells, supporting the potential of IRAK4 inhibitors to modulate c-Myc activity and enhance combinatorial therapies. This study demonstrates that IRAK4 is a therapeutic target in AML, and that combination therapies, such as with certain GSPT1-targeting CELMoDs, will be necessary to achieve maximal clinical responses.
- |||||||||| Journal: Evaluation of anti-leukemic activity and underlying mechanisms of the novel GSPT1 degrader AB138 in acute myeloid leukemia. (Pubmed Central) - Jul 30, 2025
Oral administration of AB138 significantly reduces the tumor burden in an MV-4-11-Luc xenograft model without overt toxicity. These findings demonstrate that efficient GSPT1 degradation by AB138 promtoes integrated stress signaling and downregulates the survival-promoting BCL-2 family member MCL1 and the oncogenic driver c-Myc, leading to potent antileukemic activity in vitro and in vivo and supporting further development of AB138 for AML therapy.
- |||||||||| Journal: Design and Application of Cereblon-Recruiting Prodegraders. (Pubmed Central) - Jul 16, 2025
Therefore, these prodegrader scaffolds introduce a generalizable conjugation strategy for CRBN-recruiting degraders to DAC linkers, eliminating the need for extensive degrader modifications to incorporate a conjugation handle. Overall, these findings establish the feasibility of utilizing glutamine analogs as a CRBN-recruiting prodegrader strategy and highlight their potential application in targeted drug delivery systems.
- |||||||||| Review, Journal: Research Progress in Targeting GSPT1: Molecular Glues, Bifunctional Degraders, and Antibody-Enabled Molecular Glues for Cancer Therapy. (Pubmed Central) - Jun 26, 2025
Degrading GSPT1 can induce apoptosis in cancer cells and reduce their viability, thus making GSPT1 a potential therapeutic target. This perspective aims to introduce the current research status of the mechanism of molecular glues targeting GSPT1, summarize the recent progress in and challenges for existing molecular glues, bifunctional degraders, and antibody-enabled molecular glues targeting GSPT1, and outline the development strategies for targeting GSPT1 in the treatment of cancer.
- |||||||||| Journal: Characterization of a dual degrader of MDM2 and GSPT1. (Pubmed Central) - Jun 8, 2025
In cancers that are non-responsive to MDM2 degradation alone, WB156 acts as a GSPT1 degrader to induce anti-proliferative effects. Here, we report the first MDM2/GSPT1 dual degrader that also upregulates p53 levels.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, GT19715 / Kintor Pharma, eragidomide (CC-90009) / BMS
TARGETING MUTANT TP53 ACUTE MYELOID LEUKEMIA THROUGH DISRUPTION OF MYC-GSPT1 AXIS (Poster Hall) - May 15, 2025 - Abstract #EHA2025EHA_2608;
GT19715 induced significantly greater SCR signals than CC-90009, a selective GSPT1 degrader, suggesting that dual MYC/GSPT1 degradation enhances SCR of MYC...Quiescent LSPCs exhibit sensitivity particularly to Venetoclax (Ven) (Zeng et al...GT19715 with Ven/5'-azacitidine (Aza) exhibited synergistic cell kill (Bliss index 67.67, P = 2.11e-10) in CD34+CD38- primary TP53 mutant AML LSCs (N = 7)... We identified a novel role of MYC in controlling translation termination and discovered that dual MYC/GSPT1 degradation by GT19715 profoundly synergized with Ven/Aza in TP53 mutant quiescent and proliferating AML stem/progenitor cells, resulting in substantial survival prolongation in TP53 mutant AML PDX models.
- |||||||||| pevonedistat (MLN4924) / Takeda, pomalidomide / Generic mfg.
Journal: Discovery of a novel molecular glue degrader targeting GSPT1/2 with a non-IMiD-based CRBN binder. (Pubmed Central) - Apr 19, 2025
Despite lacking the characteristic glutarimide moiety present in other CRBN-based molecular glue degraders, 4a interacts effectively with the IMiD binding site of CRBN. Structural characterization through analog synthesis further underscored the importance of specific structural features for CRBN engagement, GSPT1/2 degradation, and anti-proliferative effects, establishing 4a as a promising novel GSPT1/2 degrader with significant therapeutic potential.
- |||||||||| lenalidomide / Generic mfg., thalidomide / Generic mfg.
Humanized CRBN knockin mice enable in vivo assessment the efficacy and toxicity of CRBN-targeted protein degraders (Section 26; Poster Board No: 11) - Mar 25, 2025 - Abstract #AACR2025AACR_8833;
Pharmacokinetic analysis revealed no significant differences between hCRBN knockin and wild-type C57BL/6 mice. In vivo CC-885 treatment induced on-target toxicity, as evidenced by rapid lethality, GSPT1 degradation, and increased pathological scores in hCRBN knockin mice.Our humanized CRBN mouse model serves as a robust preclinical platform for evaluating the efficacy and toxicity of CRBN-targeted protein degraders, offering valuable insights for drug development.
- |||||||||| Drug target ID and binding site mapping in complex cellular environments using LiP-MS (Section 26; Poster Board No: 10) - Mar 25, 2025 - Abstract #AACR2025AACR_6380;
Similarly, we located binding sites for EGFR inhibitors gefitinib and afatinib on the membrane-bound EGFR protein. Additionally, we pinpointed the SMER28 binding site on the hexameric ATPase VCP, an autophagy enhancer, demonstrating the method's applicability to large protein complexes.In conclusion, LiP-MS provides a versatile toolbox for identifying drug targets and mapping binding sites within complex cellular environments.
- |||||||||| Discovery of novel, potent and orally active GSPT1 molecular glue degraders (Section 18; Poster Board No: 12) - Mar 25, 2025 - Abstract #AACR2025AACR_3172;
In fact, clinical proof of concept has been obtained with immunomodulatory drugs such as thalidomide, lenalidomide and pomalidomide, which degrade IKZF1/IKZF3...GSPT1 degrader antibody conjugates are now in clinical trials for breast cancer (ORM-5029) and AML (BMS-986497/ORM-6151)...These encouraging results have prompted us to explore a series of GSPT1 MGDs.In the present study, we describe the discovery of a series of novel, potent and orally active GSPT1 MGD targeting tumors with high GSPT1 expression...This compound demonstrates in vivo efficacy in CDX model with a favorable profile comparable to that of MRT-2359. In summary, a series of orally active GSPT1 degraders have been discovered with preclinical profile suitable for further development to manage cancers with high GSPT1 expression.
- |||||||||| TRX-214-1002 / Therapex
TRX-214-1002, An antibody drug conjugate (ADC) targeting CD33 with a novel GSPT1 molecular glue for treatment of acute myeloid leukemia (Section 18; Poster Board No: 1) - Mar 25, 2025 - Abstract #AACR2025AACR_3169;
However, clinical development of GSPT1 MGDs, such as CC-885 and CC-90009, has been hampered by off-target toxicities...The in vitro and in vivo pharmacology of TRX-214-1002 were compared with ORM-6151 (another GSPT1 MG degrader-based CD33 ADC) and Mylotarg...Collectively, TRX-214-1002 highlighted the noticeable GSPT1 degradability and enhanced antileukemic activity, particularly in TP53 mutated and venetoclax-resistant AML cell lines, along with significant antitumor activity superior to competitor ADCs. Our preclinical data suggest that TRX-214-1002 has the high potential to provide a novel treatment strategy for CD33 positive relapse/refractory AML patients.
- |||||||||| Journal: Discovery of highly potent dual GSPT1/BRD4 degraders with anti-AML activity. (Pubmed Central) - Mar 2, 2025
Furthermore, DP-15 demonstrated enhanced antitumor efficacy in mouse cell-derived xenograft (CDX) models. Our findings highlight the potential of dual BRD4 and GSPT1 degraders, such as DP-15, as effective therapeutic agents for the treatment of hematological malignancies.
- |||||||||| Journal: Degradome analysis to identify direct protein substrates of small-molecule degraders. (Pubmed Central) - Jan 18, 2025
We show that the approach efficiently operates at the timescale of TPD (hours) and we demonstrate its utility by analyzing the cyclin K degraders dCeMM2 and dCeMM4, which induce widespread transcriptional downregulation, and the GSPT1 degrader CC-885, an inhibitor of protein translation. Additionally, we apply DegMS to characterize a previously uncharacterized degrader, and identify the zinc-finger protein FIZ1 as a degraded target.
- |||||||||| sirolimus / Generic mfg.
Journal: A Dual-Target and Dual-Mechanism Design Strategy by Combining Inhibition and Degradation Together. (Pubmed Central) - Dec 2, 2024
Mammalian targets of rapamycin (mTOR) and G1 to S phase transition 1 gene (GSPT1) are overexpressed in glioblastoma, regulating vital cellular functions...YB-3-17 can safely and effectively inhibit tumor growth in mice, offering a promising direction for precision treatment of glioblastoma, representing the first attempt to combine mTOR inhibition with GSPT1 degradation. This work also demonstrates that it is conceptually possible to successfully combine the properties of small molecule inhibitors and degraders into a single molecule, killing two birds with one stone.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, GT19715 / Kintor Pharma, eragidomide (CC-90009) / BMS
Targeting Co-Regulatory Feedback Loop of MYC and GSPT1 By MYC/GSPT1 Dual Degradation Is Synthetic Lethal in Combination with Ven/Aza in TP53 Mutant Acute Myeloid Leukemia Stem and Progenitor Cells (Halls G-H (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_5272;
ASH 2022, 2023), induced significantly greater GFP signals than CC-90009, a selective GSPT1 CELMoD, suggesting that dual MYC/GSPT1 degradation enhances SCR on MYC gene...Quiescent LSPCs exhibit sensitivity particularly to Venetoclax (Ven) (Zeng et al...Indeed, the combinatorial treatment of GT19715 with Ven/5'-azacitidine (Aza) exhibited synergistic cell kill (Bliss index 67.67, P = 2.11e-10) in CD34+CD38- LSCs in primary TP53 mutant AML samples (N = 7)...The combinatorial treatment nearly eradicated these remaining AML cells in bone marrow samples in another ongoing PDX AML experiment (PDX824) carrying TP53 p.Y220C and p.G105fs, suggesting that the combinatorial approach of dual MYC/GSPT1 degradation with Ven/Aza can be an effective therapeutic approach for TP53 mutant AML. Conclusion : we identified a novel positive co-regulatory feedback loop between MYC and GSPT1, and found that dual MYC/GSPT1 degradation by GT19715 profoundly synergized in the induction of cell death in combination with Ven/Aza in both TP53 mutant quiescent and proliferating AML stem and progenitor cells.
- |||||||||| Hdz-C123A / HealZen Therap
Potent in Vitro and In Vivo Efficacy of Hdz-C123A, a GSPT1 Degrader-Antibody Conjugate Targeting CD123 in Acute Myeloid Leukemia (Room 33 (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_1664;
Ex vivo experiments revealed a stronger potency of HDZ-C123A in AML patient-derived blasts compared to CC-90009 and venetoclax...Conclusions : In summary, CDG0501, as a potent GSPT1 degrader, demonstrates potential as a next-generation payload in preclinical studies. HDZ-C123A, constructed based on CDG0501, shows promising potential as a first-in-class CD123-targeting degrader-antibody conjugate for AML treatment.
- |||||||||| doxorubicin hydrochloride / Generic mfg.
Journal: Confounding Factors in Targeted Degradation of Short-Lived Proteins. (Pubmed Central) - Jul 3, 2024
This is exemplified by the disappearance of short-lived proteins such as MCL1 and MDM2 upon GSPT1 degradation and upon treatment with cytotoxic agents such as doxorubicin. These findings have implications for target selection as well as for the type of control experiments required to conclude that a novel agent works as a bona fide targeted protein degrader.
- |||||||||| Journal: Identification of novel GSPT1 degraders by virtual screening and bioassay. (Pubmed Central) - Jun 9, 2024
These findings have implications for target selection as well as for the type of control experiments required to conclude that a novel agent works as a bona fide targeted protein degrader. Furthermore, AN5777 displayed good antiproliferative activities against U937 and OCI-AML-2
- |||||||||| lenalidomide / Generic mfg.
Journal: SuFEx-based chemical diversification for the systematic discovery of CRBN molecular glues. (Pubmed Central) - Apr 13, 2024
We synthesized over 3,000 analogs of 5'-amino lenalidomide using this approach and screened the crude products using a phenotypic screen for cell viability, identifying dozens of analogs with differentiated activity. We characterized four compounds that degrade G-to-S phase transition 1 (GSPT1) protein, providing a proof-of-concept model for SuFEx-based discovery of CRBN molecular glues.
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