論文 - 詳細
| RRC ID | 77103 |
|---|---|
| 著者 | Smith AL, Eiken AP, Skupa SA, Moore DY, Umeta LT, Smith LM, Lyden ER, D'Angelo CR, Kallam A, Vose JM, Kutateladze TG, El-Gamal D. |
| タイトル | A Novel Triple-Action Inhibitor Targeting B-Cell Receptor Signaling and BRD4 Demonstrates Preclinical Activity in Chronic Lymphocytic Leukemia. |
| ジャーナル | Int J Mol Sci |
| Abstract |
B-cell chronic lymphocytic leukemia (CLL) results from intrinsic genetic defects and complex microenvironment stimuli that fuel CLL cell growth through an array of survival signaling pathways. Novel small-molecule agents targeting the B-cell receptor pathway and anti-apoptotic proteins alone or in combination have revolutionized the management of CLL, yet combination therapy carries significant toxicity and CLL remains incurable due to residual disease and relapse. Single-molecule inhibitors that can target multiple disease-driving factors are thus an attractive approach to combat both drug resistance and combination-therapy-related toxicities. We demonstrate that SRX3305, a novel small-molecule BTK/PI3K/BRD4 inhibitor that targets three distinctive facets of CLL biology, attenuates CLL cell proliferation and promotes apoptosis in a dose-dependent fashion. SRX3305 also inhibits the activation-induced proliferation of primary CLL cells in vitro and effectively blocks microenvironment-mediated survival signals, including stromal cell contact. Furthermore, SRX3305 blocks CLL cell migration toward CXCL-12 and CXCL-13, which are major chemokines involved in CLL cell homing and retention in microenvironment niches. Importantly, SRX3305 maintains its anti-tumor effects in ibrutinib-resistant CLL cells. Collectively, this study establishes the preclinical efficacy of SRX3305 in CLL, providing significant rationale for its development as a therapeutic agent for CLL and related disorders. |
| 巻・号 | 23(12) |
| 公開日 | 2022-6-16 |
| DOI | 10.3390/ijms23126712 |
| PII | ijms23126712 |
| PMID | 35743155 |
| PMC | PMC9224275 |
| MeSH | Cell Cycle Proteins / pharmacology Humans Leukemia, Lymphocytic, Chronic, B-Cell* / pathology Nuclear Proteins Phosphatidylinositol 3-Kinases Protein Kinase Inhibitors / pharmacology Protein Kinase Inhibitors / therapeutic use Receptors, Antigen, B-Cell / metabolism Transcription Factors Tumor Microenvironment |
| IF | 4.556 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
|
| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 5 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | 9-15C(RCB2323) |