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Humanized Mcl-1 mice enable accurate preclinical evaluation of MCL-1 inhibitors destined for clinical use
| Content Provider | Scilit |
|---|---|
| Author | Brennan, Margs S. Chang, Catherine Tai, Lin Lessene, Guillaume Strasser, Andreas Dewson, Grant Kelly, Gemma L. Herold, Marco J. |
| Copyright Year | 2018 |
| Description | Myeloid cell leukemia-1 (MCL-1) is a prosurvival B-cell lymphoma 2 (BCL-2) family member required for the sustained growth of many cancers. Recently, a highly specific MCL-1 inhibitor, S63845, showing sixfold higher affinity to human compared with mouse MCL-1, has been described. To accurately test efficacy and tolerability of this BH3-mimetic (BH3-only protein mimetic) drug in preclinical cancer models, we developed a humanized Mcl-1 (huMcl-1) mouse strain in which MCL-1 was replaced with its human homolog. huMcl-1 mice are phenotypically indistinguishable from wild-type mice but are more sensitive to the MCL-1 inhibitor S63845. Importantly, nontransformed cells and lymphomas from huMcl-1;Eµ-Myc mice are more sensitive to S63845 in vitro than their control counterparts. When huMcl-1;Eµ-Myc lymphoma cells were transplanted into huMcl-1 mice, treatment with S63845 alone or alongside cyclophosphamide led to long-term remission in ∼60% or almost 100% of mice, respectively. These results demonstrate the potential of our huMcl-1 mouse model for testing MCL-1 inhibitors, allowing precise predictions of efficacy and tolerability for clinical translation. Key Points Due to the higher affinity of current MCL-1 inhibitors, huMcl-1 mice have been established. A therapeutic window for S63845 can be established in huMcl-1 mice transplanted with huMcl-1;Eµ-Myc lymphomas. Visual Abstract |
| Related Links | https://ashpublications.org/blood/article-pdf/132/15/1573/1407155/blood859405.pdf |
| Ending Page | 1583 |
| Page Count | 11 |
| Starting Page | 1573 |
| DOI | 10.1182/blood-2018-06-859405 |
| Journal | Blood |
| Issue Number | 15 |
| Volume Number | 132 |
| Language | English |
| Publisher | American Society of Hematology |
| Publisher Date | 2018-10-11 |
| Access Restriction | Open |
| Subject Keyword | Medicinal Chemistry Efficacy Tolerability S63845 Models Mcl Lymphoma Higher Affinity Bh3 Mimetic Journal: Blood (Vol- 125, Issue- 15) |
| Content Type | Text |
| Resource Type | Article |
