A-1331852 is an orally available BCL-XL selective inhibitor with a Ki value < 0.01nM [1]. A-1331852 can stimulate the exposure of phosphatidylserine (PS) in cells, induce the cleavage of caspase-3, and activate BAX and BAK, leading to rapid loss of mitochondrial membrane potential[2]. A-1331852 has been widely used to inhibit the proliferation of leukemia cells and the growth of xenograft tumors [3].
In vitro, A-1331852 treatment (1µM) for 24 hours significantly inhibited HL-60 cell viability, reduced the expression of MCL1, and induced phosphorylation of p38 MAPK[4]. Treatment with 10µM A-1331852 for 24 hours selectively eliminated senescent chondrocytes, accompanied by significant increases in nuclear condensation and cleavage of PARP protein[5]. Treatment with 10µM A-1331852 for 24 hours selectively killed senescent A549 cells and induced apoptosis of senescent A549 cells through the mitochondrial pathway[6].
In vivo, A-1331852 treatment via oral administration at a dose of 25mg/kg, twice daily for 18 days, significantly inhibited the growth of xenograft tumors in mice with fluorouracil (5-FU)-resistant HCT116 cells, without affecting body weight[7]. Oral administration of a 25mg/kg dose of A-1331852 daily for 3 weeks significantly delayed tumor growth in a lung adenocarcinoma mouse model and reduced the number of tumor-associated neutrophils (TAN)[8].
References:
[1] Leverson J D, Phillips D C, Mitten M J, et al. Exploiting selective BCL-2 family inhibitors to dissect cell survival dependencies and define improved strategies for cancer therapy[J]. Science translational medicine, 2015, 7(279): 279ra40-279ra40.
[2] Kehr S, Haydn T, Bierbrauer A, et al. Targeting BCL-2 proteins in pediatric cancer: Dual inhibition of BCL-XL and MCL-1 leads to rapid induction of intrinsic apoptosis[J]. Cancer letters, 2020, 482: 19-32.
[3] Enzenmüller S, Niedermayer A, Seyfried F, et al. Acquired venetoclax resistance in an in vivo model of B-cell precursor acute lymphoblastic leukemia is characterized by altered functions of apoptosis regulators[J]. Blood, 2023, 142: 1446.
[4] Chiou J T, Wu Y Y, Lee Y C, et al. BCL2L1 inhibitor A-1331852 inhibits MCL1 transcription and triggers apoptosis in acute myeloid leukemia cells[J]. Biochemical pharmacology, 2023, 215: 115738.
[5] Wu G, Zhang C, Xu L, et al. BAK plays a key role in A-1331852-induced apoptosis in senescent chondrocytes[J]. Biochemical and biophysical research communications, 2022, 609: 93-99.
[6] Wu G, Li X, Zhan Y, et al. BID-and BAX-mediated mitochondrial pathway dominates A-1331852-induced apoptosis in senescent A549 cells[J]. Biochemical and biophysical research communications, 2022, 627: 160-167.
[7] Kato A, Takahashi H, Asai H, et al. Bcl‑xL‑specific BH3 mimetic A‑1331852 suppresses proliferation of fluorouracil‑resistant colorectal cancer cells by inducing apoptosis[J]. Oncology Reports, 2024, 53(2): 26.
[8] Bodac A, Mayet A, Rana S, et al. Bcl-xL targeting eliminates ageing tumor-promoting neutrophils and inhibits lung tumor growth[J]. EMBO molecular medicine, 2023, 16(1): 158.