PROTAC-Mediated Dual Degradation of BCL-xL and BCL-2 Is a Highly Effective Therapeutic Strategy in Small-Cell Lung Cancer
BCL-xL and BCL-2 are validated therapeutic targets in small-cell lung cancer (SCLC). Targeting these proteins with navitoclax (formerly ABT263, a dual BCL-xL/2 inhibitor) induces dose-limiting thrombocytopenia through on-target BCL-xL inhibition in platelets. Therefore, platelet toxicity poses a bar...
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MDPI AG
2024-03-01
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| Online Access: | https://www.mdpi.com/2073-4409/13/6/528 |
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| author | Sajid Khan Lin Cao Janet Wiegand Peiyi Zhang Maria Zajac-Kaye Frederic J. Kaye Guangrong Zheng Daohong Zhou |
| author_facet | Sajid Khan Lin Cao Janet Wiegand Peiyi Zhang Maria Zajac-Kaye Frederic J. Kaye Guangrong Zheng Daohong Zhou |
| author_sort | Sajid Khan |
| collection | DOAJ |
| description | BCL-xL and BCL-2 are validated therapeutic targets in small-cell lung cancer (SCLC). Targeting these proteins with navitoclax (formerly ABT263, a dual BCL-xL/2 inhibitor) induces dose-limiting thrombocytopenia through on-target BCL-xL inhibition in platelets. Therefore, platelet toxicity poses a barrier in advancing the clinical translation of navitoclax. We have developed a strategy to selectively target BCL-xL in tumors, while sparing platelets, by utilizing proteolysis-targeting chimeras (PROTACs) that hijack the cellular ubiquitin proteasome system for target ubiquitination and subsequent degradation. In our previous study, the first-in-class BCL-xL PROTAC, called DT2216, was shown to have synergistic antitumor activities when combined with venetoclax (formerly ABT199, BCL-2-selective inhibitor) in a BCL-xL/2 co-dependent SCLC cell line, NCI-H146 (hereafter referred to as H146), in vitro and in a xenograft model. Guided by these findings, we evaluated our newly developed BCL-xL/2 dual degrader, called 753b, in three BCL-xL/2 co-dependent SCLC cell lines and the H146 xenograft models. 753b was found to degrade both BCL-xL and BCL-2 in these cell lines. Importantly, it was considerably more potent than DT2216, navitoclax, or DT2216 + venetoclax in reducing the viability of BCL-xL/2 co-dependent SCLC cell lines in cell culture. In vivo, 5 mg/kg weekly dosing of 753b was found to lead to significant tumor growth delay, similar to the DT2216 + venetoclax combination in H146 xenografts, by degrading both BCL-xL and BCL-2. Additionally, 753b administration at 5 mg/kg every four days induced tumor regressions. At this dosage, 753b was well tolerated in mice, without observable induction of severe thrombocytopenia as seen with navitoclax, and no evidence of significant changes in mouse body weights. These results suggest that the BCL-xL/2 dual degrader could be an effective and safe therapeutic for a subset of SCLC patients, warranting clinical trials in future. |
| first_indexed | 2024-04-24T18:27:08Z |
| format | Article |
| id | doaj.art-a29e79df61604c65a48287af106a045c |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-04-24T18:27:08Z |
| publishDate | 2024-03-01 |
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| record_format | Article |
| series | Cells |
| spelling | doaj.art-a29e79df61604c65a48287af106a045c2024-03-27T13:30:40ZengMDPI AGCells2073-44092024-03-0113652810.3390/cells13060528PROTAC-Mediated Dual Degradation of BCL-xL and BCL-2 Is a Highly Effective Therapeutic Strategy in Small-Cell Lung CancerSajid Khan0Lin Cao1Janet Wiegand2Peiyi Zhang3Maria Zajac-Kaye4Frederic J. Kaye5Guangrong Zheng6Daohong Zhou7Department of Biochemistry & Structural Biology, Long School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USADepartment of Biochemistry & Structural Biology, Long School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USADepartment of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USADepartment of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL 32610, USADepartment of Anatomy & Cell Biology, College of Medicine, University of Florida, Gainesville, FL 32610, USADivision of Hematology and Oncology, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USADepartment of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL 32610, USADepartment of Biochemistry & Structural Biology, Long School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USABCL-xL and BCL-2 are validated therapeutic targets in small-cell lung cancer (SCLC). Targeting these proteins with navitoclax (formerly ABT263, a dual BCL-xL/2 inhibitor) induces dose-limiting thrombocytopenia through on-target BCL-xL inhibition in platelets. Therefore, platelet toxicity poses a barrier in advancing the clinical translation of navitoclax. We have developed a strategy to selectively target BCL-xL in tumors, while sparing platelets, by utilizing proteolysis-targeting chimeras (PROTACs) that hijack the cellular ubiquitin proteasome system for target ubiquitination and subsequent degradation. In our previous study, the first-in-class BCL-xL PROTAC, called DT2216, was shown to have synergistic antitumor activities when combined with venetoclax (formerly ABT199, BCL-2-selective inhibitor) in a BCL-xL/2 co-dependent SCLC cell line, NCI-H146 (hereafter referred to as H146), in vitro and in a xenograft model. Guided by these findings, we evaluated our newly developed BCL-xL/2 dual degrader, called 753b, in three BCL-xL/2 co-dependent SCLC cell lines and the H146 xenograft models. 753b was found to degrade both BCL-xL and BCL-2 in these cell lines. Importantly, it was considerably more potent than DT2216, navitoclax, or DT2216 + venetoclax in reducing the viability of BCL-xL/2 co-dependent SCLC cell lines in cell culture. In vivo, 5 mg/kg weekly dosing of 753b was found to lead to significant tumor growth delay, similar to the DT2216 + venetoclax combination in H146 xenografts, by degrading both BCL-xL and BCL-2. Additionally, 753b administration at 5 mg/kg every four days induced tumor regressions. At this dosage, 753b was well tolerated in mice, without observable induction of severe thrombocytopenia as seen with navitoclax, and no evidence of significant changes in mouse body weights. These results suggest that the BCL-xL/2 dual degrader could be an effective and safe therapeutic for a subset of SCLC patients, warranting clinical trials in future.https://www.mdpi.com/2073-4409/13/6/528BCL-xLBCL-2PROTACapoptosissmall-cell lung cancer |
| spellingShingle | Sajid Khan Lin Cao Janet Wiegand Peiyi Zhang Maria Zajac-Kaye Frederic J. Kaye Guangrong Zheng Daohong Zhou PROTAC-Mediated Dual Degradation of BCL-xL and BCL-2 Is a Highly Effective Therapeutic Strategy in Small-Cell Lung Cancer Cells BCL-xL BCL-2 PROTAC apoptosis small-cell lung cancer |
| title | PROTAC-Mediated Dual Degradation of BCL-xL and BCL-2 Is a Highly Effective Therapeutic Strategy in Small-Cell Lung Cancer |
| title_full | PROTAC-Mediated Dual Degradation of BCL-xL and BCL-2 Is a Highly Effective Therapeutic Strategy in Small-Cell Lung Cancer |
| title_fullStr | PROTAC-Mediated Dual Degradation of BCL-xL and BCL-2 Is a Highly Effective Therapeutic Strategy in Small-Cell Lung Cancer |
| title_full_unstemmed | PROTAC-Mediated Dual Degradation of BCL-xL and BCL-2 Is a Highly Effective Therapeutic Strategy in Small-Cell Lung Cancer |
| title_short | PROTAC-Mediated Dual Degradation of BCL-xL and BCL-2 Is a Highly Effective Therapeutic Strategy in Small-Cell Lung Cancer |
| title_sort | protac mediated dual degradation of bcl xl and bcl 2 is a highly effective therapeutic strategy in small cell lung cancer |
| topic | BCL-xL BCL-2 PROTAC apoptosis small-cell lung cancer |
| url | https://www.mdpi.com/2073-4409/13/6/528 |
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