B-cell specific Moloney murine leukemia virus integration site 1 (BMI-1) has pleiotropic function in several cellular processes, including DNA damage, apoptosis, senescence, and self-renewal of stem cells. BMI-1 also plays a central role in cancer stem cell growth and survival in various neoplasia, PTC596 is a small molecule selective inhibitor of BMI1. PTC596 can inhibited proliferation of mantle cell lymphoma (MCL) cell lines, including REC-1, NCEB-1, MINO, MAVER-1, JVM-2, Granta-519, Jeko-1, and Z-138 with IC50 values ranging in 68-340 nM and EC50 values ranging in 150-507 nM, PTC596 at concentration of 300 nM induced activation, caspase-3 cleavage, mitochondrial membrane potential loss and MCL-1 levels decreased in Z-138 and REC-1 cells. These data suggested PTC596 induces mitochondrial apoptosis in MCL cells through down-regulation of MCL-1[1]. PTC596 at concentration of 0.1 and 1μM reduced cell viability and induced a G2M arrest in human PDA lines Aspc1, Mia PaCa-2, and Panc1. PTC596 also induced the M-phase marker phospho-histone H3 (PH3) accumulation in these PDA cells. These data demonstrated that PTC596 acts as a potent inducer of mitotic arrest in multiple PDA cell lines[2]. In vivo, administration of PTC596 at 15 mg/kg twice weekly led to a 48.9% reduction of bone marrow multiple myeloma infiltration and weekly treatment with PTC596 at a dose of 30 mg/kg led to a complete eradication of multiple myeloma cells in 5TGM.1 murine model of myeloma[3]. Oral administration of PTC596 at 12.5 mg/kg twice a week for 45 days slowed tumor growth modestly in nu/nu mice bearing Capan-1 xenograft tumors. Oral administration of 17 mg/kg PTC596 did not affect survival, but the combination of the PTC596 and gemcitabine in a synergistic way improved survival in nu/nu mice bearing Capan-1 xenograft tumors[2].
作用机制
PTC596 induces phosphorylation of BMI-1 at two N-terminal sites, leading to accelerated degradation of BMI-1[1].
Unesbulin 细胞实验
Cell Line
Concentration
Treated Time
Description
References
AML cell lines
200 nM
20 hours
Evaluate the effect of Unesbulin as a single agent and in combination with Venetoclax on apoptosis and cell death in leukemic cells
Int J Mol Sci. 2022 Oct 20;23(20):12587.
UM-HACC-6
0-100 nM
24 hours
To evaluate the effect of PTC596 on ACC stem cell fraction, results showed PTC596 decreased the fraction of ALDHhighCD44high cells.
Oral Oncol. 2023 Jul;142:106437
UM-HACC-14
0-100 nM
24 hours
To evaluate the effect of PTC596 on ACC stem cell fraction, results showed PTC596 decreased the fraction of ALDHhighCD44high cells.
Oral Oncol. 2023 Jul;142:106437
UM-HACC-2A
0-100 nM
24 hours
To evaluate the effect of PTC596 on ACC stem cell fraction, results showed PTC596 decreased the fraction of ALDHhighCD44high cells.
Oral Oncol. 2023 Jul;142:106437
SKLU1 cells
1 µM
24, 48, 72 hours
To evaluate the effect of PTC596 on BMI-1 protein levels, showing the presence of hyperphosphorylated BMI-1 form.
Commun Biol. 2021 Apr 14;4(1):370
A549 cells
1 µM
24, 48, 72 hours
To evaluate the effect of PTC596 on BMI-1 protein levels, showing the presence of hyperphosphorylated BMI-1 form.
Commun Biol. 2021 Apr 14;4(1):370
HTLA-ER
35 nM
72 hours
PTC596 significantly reduced the viability of HTLA-ER cells and decreased BMI-1 expression levels
Antioxidants (Basel). 2023 Dec 19;13(1):3
HTLA-230
35 nM
72 hours
PTC596 significantly reduced the viability of HTLA-230 cells and decreased BMI-1 expression levels
Antioxidants (Basel). 2023 Dec 19;13(1):3
Unesbulin 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
KP mouse model (Kras+/G12D;Trp53−/−)
Oral gavage
12 mg/kg
Twice per week for one month
To evaluate the effect of PTC596 on KRAS-mutant tumor growth, showing significant reduction in tumor volume.
Commun Biol. 2021 Apr 14;4(1):370
SCID mice
UM-PDX-HACC-5 tumor model
Intraperitoneal injection
5 mg/kg
Twice a week for 5 days
To evaluate the effect of PTC596 on CSC fraction in ACC tumors, results showed PTC596 decreased the fraction of ALDHhighCD44high cells.
Oral Oncol. 2023 Jul;142:106437
NSG mice
MOLM-13 xenograft model
Oral
5 mg/kg
Every 3 days for 13 days
PTC596 significantly reduced circulating human CD45-positive cells and prolonged mouse survival
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