The BET (bromodomain and extra terminal) family of proteins, BRD2, BRD3, BRD4 and BRDT, are chromatin readers that regulate transcription of genes by binding to acetylated lysine residues on tails of histones in chromatin[1]. PLX51107 is a potent and selective BET inhibitor, with Kd values of 1.6, 2.1, 1.7, and 5 nM for BD1 and 5.9, 6.2, 6.1, and 120 nM for BD2 of BRD2, BRD3, BRD4, and BRDT, respectively. PLX51107 prevented CpG-induced cell proliferation in primary Chronic lymphocytic leukemia (CLL) cells in a dose dependent fashion under both continuous and washout conditions. Oral gavage of PLX51107 (20 mg/kg daily) for eight days in mouse model of CLL significantly reduced leukemic disease burden in peripheral blood and spleen with modulation of BRD4 targets, compared to vehicle-treated mice[2]. In mice bearing UM001 xenograft tumors, PLX51107 (90 mg/kg) and AZD4547 (5 mg/kg) alone suppressed tumor size moderately but the combination of PLX51107 and AZD4547 significantly decreased tumor size after 2 weeks of treatment, in comparison with the control[3].
In BCL-2-high DLBCL cell lines, PLX51107 and PLX2853 showed limited efficacy alone but exhibited synergistic effects when combined with the BH3 mimetic ABT199, significantly enhancing apoptosis.
Blood Adv. 2020 Jul 28;4(14):3316-3328.
HBLAK
0.6 µM
72 hours
PLX51107 inhibited cell growth, caused DNA damage, and blocked DNA repair response in UC cells
Cancers (Basel). 2021 Mar 18;13(6):1376.
UM-UC-3
8.8 µM
72 hours
PLX51107 inhibited cell growth, caused DNA damage, and blocked DNA repair response in UC cells
Cancers (Basel). 2021 Mar 18;13(6):1376.
VM-CUB1
2 µM
72 hours
PLX51107 inhibited cell growth, caused DNA damage, and blocked DNA repair response in UC cells
Cancers (Basel). 2021 Mar 18;13(6):1376.
THJ-16T cells
500 nM
5 days
Evaluate the effect of PLX on cell proliferation, results showed that PLX inhibited the proliferation of THJ-16T cells, reducing cell numbers by 88.4%.
Endocr Relat Cancer. 2019 Sep;26(9):739-750.
THJ-11T cells
500 nM
5 days
Evaluate the effect of PLX on cell proliferation, results showed that PLX inhibited the proliferation of THJ-11T cells, reducing cell numbers by 88.9%.
Endocr Relat Cancer. 2019 Sep;26(9):739-750.
Primary CLL cells
1μM
4 hours
To assess the effect of PLX51107 on BRD4 binding, results showed significant reduction in BRD4 load at enhancer regions
Cancer Discov. 2018 Apr;8(4):458-477.
Omm1.3 cells
0.5 μmol/L
48 hours
Validate the synergistic effect of PTL with PLX51107, inhibiting NF-κB signaling and inducing apoptosis.
Cancer Res. 2019 May 1;79(9):2415-2425.
92.1 cells
0.04-5 μmol/L
72 hours
Evaluate the combinatorial therapeutic effects of PLX51107 with a compound library, identifying NF-κB inhibitors PTL and PDTC as synergistic with PLX51107.
Cancer Res. 2019 May 1;79(9):2415-2425.
OCI-AML3
1 µM
96 hours
To evaluate the effect of PLX51107 on AML cell viability, results showed that PLX51107 reduced AML cell viability
Exp Hematol Oncol. 2024 Mar 4;13(1):27.
MOLM-13
1 µM
96 hours
To evaluate the effect of PLX51107 on AML cell viability, results showed that PLX51107 reduced AML cell viability
Exp Hematol Oncol. 2024 Mar 4;13(1):27.
MV4-11
1 µM
96 hours
To evaluate the effect of PLX51107 on AML cell viability, results showed that PLX51107 reduced AML cell viability
Exp Hematol Oncol. 2024 Mar 4;13(1):27.
M238 cells
1, 2, and 4 μM
24 hours to 3 weeks
PLX51107 combined with BRAFi/MEKi significantly inhibited the growth of M238 cells and reduced S-phase entry.
Br J Cancer. 2020 Mar;122(6):789-800.
1205Lu cells
1, 2, and 4 μM
24 hours to 3 weeks
PLX51107 combined with BRAFi/MEKi significantly inhibited the growth of 1205Lu cells and reduced S-phase entry.
Br J Cancer. 2020 Mar;122(6):789-800.
A375 cells
1, 2, and 4 μM
24 hours to 3 weeks
PLX51107 combined with BRAFi/MEKi significantly inhibited the growth of A375 cells and reduced S-phase entry.
Br J Cancer. 2020 Mar;122(6):789-800.
OCI-AML3 cells
250 nM
3 hours
Evaluate the inhibitory effect of PLX51107 on MYC expression
Haematologica. 2021 Apr 1;106(4):1022-1033.
MOLM-14 cells
79 nM
Evaluate the inhibitory effect of PLX51107 on FLT3-ITD mutated AML cells
Haematologica. 2021 Apr 1;106(4):1022-1033.
MV4-11 cells
62 nM
Evaluate the inhibitory effect of PLX51107 on FLT3-ITD mutated AML cells
Haematologica. 2021 Apr 1;106(4):1022-1033.
Em-myc lymphoma cell lines
1000 nM
48 hours
PLX51107 and PLX2853 induced apoptosis by upregulating BIM protein and suppressing the miR-17~92 cluster, resulting in cytotoxic responses in BCL-2-low MYC-driven lymphomas.
Blood Adv. 2020 Jul 28;4(14):3316-3328.
Rheumatoid arthritis patient CD14+ monocytes
50, 250 nM
48 hours
To evaluate the effect of PLX51107 on FcγR expression in monocytes from rheumatoid arthritis patients. Results showed that PLX51107 significantly downregulated FcγRIIa, FcγRIIb, FcγRIIIa, and γ chain mRNA expression, while upregulating FcγRIa expression.
Int J Mol Sci. 2023 Apr 21;24(8):7623.
Healthy donor CD14+ monocytes
50, 100, 200, 250 nM
24 hours
To evaluate the effect of PLX51107 on the transcriptional expression of FcγRIIa, FcγRIIb, FcγRIIIa, and FcεRIγ. Results showed that PLX51107 significantly downregulated FcγRIIa, FcγRIIb, and FcγRIIIa mRNA expression, while upregulating FcγRIa expression.
Int J Mol Sci. 2023 Apr 21;24(8):7623.
PLX51107 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Nude mice
Xenograft model
Oral
24 mg/kg/day
Once daily for 24 days or 48 days
Evaluate the inhibitory effect of PLX on tumor growth, results showed that PLX significantly inhibited the growth of xenograft tumors.
Endocr Relat Cancer. 2019 Sep;26(9):739-750.
Mice
Eμ-TCL1 transgenic mouse model
Oral gavage
20 mg/kg
Once daily for eight days
To assess the effect of PLX51107 on leukemia burden, results showed significant reduction in leukemic cells in peripheral blood and spleen
Cancer Discov. 2018 Apr;8(4):458-477.
Athymic nu/nu mice
R-Omm1.3 xenograft model
Oral and intraperitoneal injection
20 mg/kg orally
Three times a week for 5 weeks
Evaluate the effect of PLX51107 combined with PTL on BETi-resistant tumors, showing significant inhibition of tumor growth.
Cancer Res. 2019 May 1;79(9):2415-2425.
NSG mice
MOLM-13-luciferase xenograft model
Oral gavage
20 mg/kg
Daily administration until the end of the experiment
To evaluate the anti-leukemic effect of PLX51107 in vivo, results showed that PLX51107 significantly prolonged the survival of mice
Exp Hematol Oncol. 2024 Mar 4;13(1):27.
Nude mice
1205Lu and A375 xenograft models
Oral
90 ppm
Intermittent dosing (2 days on/5 days off)
Intermittent PLX51107 combined with BRAFi/MEKi treatment significantly delayed tumor recurrence and improved animal survival.
Br J Cancer. 2020 Mar;122(6):789-800.
SCID mice
MV4-11 xenograft model
Oral
10, 20, 40 mg/kg
Once daily for 14 days
Evaluate the anti-tumor effect of PLX51107 as a single agent in FLT3-ITD AML xenograft model
Haematologica. 2021 Apr 1;106(4):1022-1033.
Mice
Em-myc lymphoma model
Oral gavage
10 mg/kg
Once daily, 5 consecutive days/week
PLX51107 and PLX2853 showed significant therapeutic effects in wild-type Em-myc lymphoma models but limited efficacy in BCL-2-high models. Combination with the BH3 mimetic ABT199 significantly enhanced tumor control.
Blood Adv. 2020 Jul 28;4(14):3316-3328.
DBA mice
Collagen-induced arthritis model
Oral gavage
10 mg/kg
Three times per week for 5 weeks
To evaluate the effect of PLX51107 on FcγR expression and arthritis symptoms in vivo. Results showed that PLX51107 significantly reduced footpad swelling and downregulated FcγR expression in monocytes and macrophages in the spleen.
Int J Mol Sci. 2023 Apr 21;24(8):7623.
Mice
BrafV600E, Ptennull, Cdkn2dnul1 YUMM1.7 tumor model
Oral
557-1500 ng/ml
12 days
PLX51107 significantly delayed melanoma growth, reduced the frequency of tumor-infiltrating Tregs, increased the CD8/Tregs ratio, and decreased PD1 expression on CD8+ T cells. Combined with anti-PD-L1, it significantly inhibited tumor growth.
United States, New York
... 展开 >>
Columbia University Medical Center
Completed
New York, New York, United States, 10032
United States, Ohio
The Ohio State University Stephanie Spielman Comprehensive Breast Center
Recruiting
Columbus, Ohio, United States, 43212
United States, Pennsylvania
Thomas Jefferson University
Completed
Philadelphia, Pennsylvania, United States, 19107
United States, South Carolina
MUSC/ Hollings Cancer Center
Completed
Charleston, South Carolina, United States, 29425
United States, Texas
South Texas Accelerated Research Therapeutics
Completed
San Antonio, Texas, United States, 78229 收起 <<
United States, New York
... 展开 >>
Columbia University Medical Center
Completed
New York, New York, United States, 10032
United States, Ohio
The Ohio State University Stephanie Spielman Comprehensive Breast Center
Recruiting
Columbus, Ohio, United States, 43212
United States, Pennsylvania
Thomas Jefferson University
Completed
Philadelphia, Pennsylvania, United States, 19107
United States, South Carolina
MUSC/ Hollings Cancer Center
Completed
Charleston, South Carolina, United States, 29425
United States, Texas
South Texas Accelerated Research Therapeutics
Completed
San Antonio, Texas, United States, 78229 收起 <<
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