Small molecule targeting of FBXO21 mediated p85αubiquitylation in acute myeloid leukemia
Dobish, K. K.; Vishwakarma, S.; Peters, H. C.; Winship, C. B.; Alvarado, D.; Hyde, R. K.; Natarajan, A.; Buckley, S. M.
Show abstract
PI3K inhibitors that target the catalytic sub-unit p110 are used in cancer therapy to inhibit overactive PI3K signaling pathway. However, their clinical use is limited by severe adverse effects and development of resistance, highlighting the need for further research on regulation of the PI3K pathway. We have identified that FBXO21 ubiquitinates regulatory PI3K subunit p85, and silencing of FBXO21 inhibits canonical PI3K signaling. To target FBXO21, we developed a small molecule designed to interfere with substrate:ligase interaction. Our novel small molecule effectively blocks p85 ubiquitination leading to decreased PI3K pathway activation and cell death in acute myeloid leukemia (AML). Moreover, our studies demonstrate selectivity for AML cells over healthy counterparts, and elimination of AML in vivo, emphasizing FBXO21s potential as a promising therapeutic target for AML. Targeting substrate:ligase interactions provide new avenues for drug discovery that may enhance the efficacy of current therapies and benefits for improving patient outcomes. STATEMENT OF SIGNIFICANCEOur studies highlight the potential of the ubiquitin E3 ligase FBXO21 as an alternative therapeutic target for the PI3K signaling pathway, not only in AML but in cancers with aberrant PI3K signaling.
Matching journals
The top 12 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Nintedanib Targets KIT D816V Neoplastic Cells Derived from Induced Pluripotent Stem cells of Systemic Mastocytosis 95%
- BRG1/BRM inhibitor targets AML stem cells and exerts superior preclinical efficacy combined with BET or Menin inhibitor 94%
- Mutant-SETBP1 activates transcription of Myc programs to accelerate CSF3R-driven myeloproliferative neoplasms 93%
Similar papers in this journal
- Momelotinib is a highly potent inhibitor of FLT3-mutant AML 96%
- Monosomy 7/del(7q) Cause Sensitivity to Inhibitors of Nicotinamide Phosphoribosyltransferase in Acute Myeloid Leukemia 94%
- Resistance mechanism to Notch inhibition and combination therapy in human T cell acute lymphoblastic leukemia 93%
Similar papers in this journal
- A drug's most potent target is not necessarily the source of its anti-cancer activity 93%
- OST Catalytic Subunit Redundancy Enables Therapeutic Targeting of N-Glycosylation 93%
- Structure-aided development of small molecule inhibitors of ENPP1, the extracellular phosphodiesterase of the immunotransmitter cGAMP 92%
Similar papers in this journal
- A small molecule inhibitor of RNA-binding protein IGF2BP3 shows anti-leukemic activity 95%
- The STAT3-VDAC1 Axis Modulates Mitochondrial Function and Plays a Critical Role in the Survival of Acute Myeloid Leukemia Cells 94%
- Inducing synthetic lethality for selective targeting of acute myeloid leukemia cells harboring STAG2 mutations 92%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.