2. Academic Validation
  3. A selective BCL-XL PROTAC degrader achieves safe and potent antitumor activity

A selective BCL-XL PROTAC degrader achieves safe and potent antitumor activity

  • Nat Med. 2019 Dec;25(12):1938-1947. doi: 10.1038/s41591-019-0668-z.
Sajid Khan  # 1,  Xuan Zhang  # 2,  Dongwen Lv  # 1,  Qi Zhang 3,  Yonghan He 1,  Peiyi Zhang 2,  Xingui Liu 1,  Dinesh Thummuri 1,  Yaxia Yuan 1,  Janet S Wiegand 1,  Jing Pei 1,  Weizhou Zhang 4,  Abhisheak Sharma 5,  Christopher R McCurdy 2,  Vinitha M Kuruvilla 3,  Natalia Baran 3,  Adolfo A Ferrando 6,  Yong-Mi Kim 7,  Anna Rogojina 8,  Peter J Houghton 8,  Guangcun Huang 9,  Robert Hromas 9,  Marina Konopleva 3,  Guangrong Zheng 10,  Daohong Zhou 11
Affiliations

Affiliations

  • 1 Department of Pharmacodynamics, University of Florida, Gainesville, FL, USA.
  • 2 Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, USA.
  • 3 Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
  • 4 Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA.
  • 5 Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, USA.
  • 6 Department of Pediatrics, Pathology, Cell Biology and Systems of Biology and Institute for Cancer Genetics, Columbia University, New York, NY, USA.
  • 7 Department of Pediatrics, Children's Hospital Los Angeles, Los Angeles, CA, USA.
  • 8 Greehey Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
  • 9 Department of Medicine, the Long School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
  • 10 Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, USA. [email protected].
  • 11 Department of Pharmacodynamics, University of Florida, Gainesville, FL, USA. [email protected].
  • # Contributed equally.
PMID: 31792461 DOI: 10.1038/s41591-019-0668-z
Abstract

B-cell lymphoma extra large (BCL-XL) is a well-validated Cancer target. However, the on-target and dose-limiting thrombocytopenia limits the use of BCL-XL inhibitors, such as ABT263, as safe and effective Anticancer agents. To reduce the toxicity of ABT263, we converted it into DT2216, a BCL-XL proteolysis-targeting chimera (PROTAC), that targets BCL-XL to the Von Hippel-Lindau (VHL) E3 ligase for degradation. We found that DT2216 was more potent against various BCL-XL-dependent leukemia and Cancer cells but considerably less toxic to platelets than ABT263 in vitro because VHL is poorly expressed in platelets. In vivo, DT2216 effectively inhibits the growth of several xenograft tumors as a single agent or in combination with other chemotherapeutic agents, without causing appreciable thrombocytopenia. These findings demonstrate the potential to use PROTAC technology to reduce on-target drug toxicities and rescue the therapeutic potential of previously undruggable targets. Furthermore, DT2216 may be developed as a safe first-in-class Anticancer agent targeting BCL-XL.

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