2. Academic Validation
  3. Novel potent molecular glue degraders against broad range of hematological cancer cell lines via multiple neosubstrates degradation

Novel potent molecular glue degraders against broad range of hematological cancer cell lines via multiple neosubstrates degradation

  • J Hematol Oncol. 2024 Sep 2;17(1):77. doi: 10.1186/s13045-024-01592-z.
Pengyun Li # 1 2,  Xiaotong Hu # 1 2,  Zhiya Fan # 3,  Shiyang Sun 1 2,  Qijie Ran 4 5,  Ting Wei 1 2,  Pengli Wei 1 2,  Qiyu Jiang 4,  Jian Yan 1 2,  Ning Yang 1 2,  Changkai Jia 1 2,  Tingting Yang 6,  Yaqiu Mao 1 2,  Xu Cai 1 2,  Tingting Xu 1 2,  Zhiyuan Zhao 1 2,  Xiaohong Qian 3,  Weijie Qin 3,  Xiaomei Zhuang 7,  Feng Fan 8,  Junhai Xiao 9 10,  Zhibing Zheng 11 12,  Song Li 1 2
Affiliations

Affiliations

  • 1 National Engineering Research Center for Strategic Drugs, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, China.
  • 2 State Key Laboratory of National Security Specially Needed Medicines, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, China.
  • 3 State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China.
  • 4 Department of Clinical Laboratory, Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China.
  • 5 Department of Hematology, General Hospital of Central Theater Command, Wuhan, 430012, China.
  • 6 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China.
  • 7 State Key Laboratory of National Security Specially Needed Medicines, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, China. xiaomeizhuang@163.com.
  • 8 Department of Clinical Laboratory, Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China. fengfanbio@126.com.
  • 9 National Engineering Research Center for Strategic Drugs, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, China. xiaojunhai@139.com.
  • 10 State Key Laboratory of National Security Specially Needed Medicines, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, China. xiaojunhai@139.com.
  • 11 National Engineering Research Center for Strategic Drugs, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, China. zzbcaptain@aliyun.com.
  • 12 State Key Laboratory of National Security Specially Needed Medicines, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, China. zzbcaptain@aliyun.com.
  • # Contributed equally.
PMID: 39218923 DOI: 10.1186/s13045-024-01592-z
Abstract

Background: Targeted protein degradation of neosubstrates plays a crucial role in hematological Cancer treatment involving immunomodulatory imide drugs (IMiDs) therapy. Nevertheless, the persistence of inevitable drug resistance and hematological toxicities represents a significant obstacle to their clinical effectiveness.

Methods: Phenotypic profiling of a small molecule compounds library in multiple hematological Cancer cell lines was conducted to screen for hit degraders. Molecular dynamic-based rational design and cell-based functional assays were conducted to develop more potent degraders. Multiple myeloma (MM) tumor xenograft models were employed to investigate the antitumor efficacy of the degraders as single or combined agents with standard of care agents. Unbiased proteomics was employed to identify multiple therapeutically relevant neosubstrates targeted by the degraders. MM patient-derived cell lines (PDCs) and a panel of solid Cancer cell lines were utilized to investigate the effects of candidate degrader on different stage of MM cells and solid malignancies. Unbiased proteomics of IMiDs-resistant MM cells, cell-based functional assays and RT-PCR analysis of clinical MM specimens were utilized to explore the role of BRD9 associated with IMiDs resistance and MM progression.

Results: We identified a novel Cereblon (CRBN)-dependent lead degrader with phthalazinone scaffold, MGD-4, which induced the degradation of Ikaros proteins. We further developed a novel potent candidate, MGD-28, significantly inhibited the growth of hematological Cancer cells and induced the degradation of IKZF1/2/3 and CK1α with nanomolar potency via a Cullin-CRBN dependent pathway. Oral administration of MGD-4 and MGD-28 effectively inhibited MM tumor growth and exhibited significant synergistic effects with standard of care agents. MGD-28 exhibited preferentially profound cytotoxicity towards MM PDCs at different disease stages and broad antiproliferative activity in multiple solid malignancies. BRD9 modulated IMiDs resistance, and the expression of BRD9 was significant positively correlated with IKZF1/2/3 and CK1α in MM specimens at different stages. We also observed pronounced synergetic efficacy between the BRD9 Inhibitor and MGD-28 for MM treatment.

Conclusions: Our findings present a strategy for the multi-targeted degradation of Ikaros proteins and CK1α against hematological cancers, which may be expanded to additional targets and indications. This strategy may enhance efficacy treatment against multiple hematological cancers and solid tumors.

Keywords

Cereblon; Drug resistance; Hematological cancer; IMIDs; Molecular glue; Neosubstrate; Rational drug design.

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