Table 1 Agents targeting NOTCH1 pathway in T-ALL
From: Advances of target therapy on NOTCH1 signaling pathway in T-cell acute lymphoblastic leukemia
Name | Target | Mechanism | Type of cancer | Phase | NCT number/publication date | Assessment |
|---|---|---|---|---|---|---|
MK-0752 | γ-Secretase | Induce G0/G1 cell cycle arrest and inhibit cell proliferation | T-ALL | I | 2006 | Transient anti-leukemia effect but severe diarrhea |
PF-03084014 | γ-Secretase | Inhibit ICN1 levels and the expression of Notch target genes | T-ALL or T-cell lymphoblastic lymphoma | I | NCT00878189 | 1/8 achieved complete remission lasting about 3 months and the most common adverse effects were nausea and vomiting |
BMS-906024 | γ-Secretase | γ-Secretase inhibitor screened by efficacy/tolerance profile | T-ALL or T-cell lymphoblastic lymphoma | I | NCT01363817 | 32% showed at least a 50% reduction in bone marrow blasts and had tolerable side effects |
MRK-560 | PSEN1 of γ-Secretase | Selective γ-Secretase inhibitor, mainly target PSEN1 in the γ-secretase complex | T-ALL | Preclinical | July 1, 2019 | Improved survival and did not show obvious gastrointestinal pathological |
G1254023X | ADAM | Prevent ADAM protease cleavage Notch receptor at the S2 site | T-ALL | Preclinical | August 20, 2015 | Inhibited the activation of NOTCH1 signaling pathway and induce apoptosis |
OMP-52M51 | NRR | Prevent ligand-free activation of NOTCH1 receptors | T-ALL | Preclinical | July 23, 2013 | Prolonged survival time but had drug resistance |
MAb 604.107 | NRR | Distinguish the conformation of the NRR region between mutant NOTCH1 and wild-type NOTCH1 | T-ALL | Preclinical | June 5, 2015 | Inhibited T-ALL leukemia-initiating cells |
SAHM1 | ICN1-CSL-MAML complex | Block the formation of ICN1-CSL-MAML complex, and inhibit the activation of NOTCH1 target gene expression | T-ALL | Preclinical | November 12, 2009 | Inhibited leukemic progression and NOTCH1 signaling |
Thapsigargicin | SERCA | Induce the depletion of endoplasmic reticulum calcium ions and oxidative stress, which ultimately leads to apoptosis | T-ALL | Preclinical | March 18, 2013 | Effective but severe cardiotoxicity |
JQ-FT | SERCA | Combine folic acid and thapsigargicin with a cleavable bond to achieve leukemia-specific delivery of thapsigargicin | T-ALL | Preclinical | January 2, 2018 | Dual selectivity: targeting NOTCH1 mutations and targeting leukemia cells, but Complex process and poor practicality |
CJ | SERCA | Target NOTCH1 HD domain mutant T-ALL, induce T-ALL cell death | T-ALL | Preclinical | January 28, 2016 | Mainly target NOTCH1 HD domain mutation but weak effect on cells with mutations in other domains of NOTCH1 |
CAD204520 | SERCA | Retain the anti-NOTCH1 tumor characteristics while inhibiting thapsigargicin-resistant cell lines | T-ALL | Preclinical | June 18, 2020 | Effective and had tolerable side effects |