| RRC ID |
77103
|
| Author |
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.
|
| Title |
A Novel Triple-Action Inhibitor Targeting B-Cell Receptor Signaling and BRD4 Demonstrates Preclinical Activity in Chronic Lymphocytic Leukemia.
|
| Journal |
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.
|
| Volume |
23(12)
|
| Published |
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
|
| Resource |
| Human and Animal Cells |
9-15C(RCB2323) |
