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Polycomb complex protein BMI-1 (also known as PCGF4 or RNF51) is a protein that in humans is encoded by the BMI1 gene (B cell-specific Moloney murine leukemia virus integration site 1), a polycomb ring finger oncogene. BMI1 has been reported as an oncogene by regulating p16 and p19, which are cell cycle inhibitor genes.

BMI-1 interacts with several signaling containing Wnt, Akt, Notch, Hedgehog and receptor tyrosine kinase (RTK) pathway. In Ewing sarcoma family of tumors (ESFT), the knockdown of BMI-1 gene would greatly influence the Notch and Wnt signaling pathway which are important for ESFT formation and development. BMI-1 also mediates the effect of Hedgehog signaling pathway on mammary stem cell proliferation, and modulation of Bmi-1 expression in mammosphere-initiating cells alters mammary development in a humanized nonobese diabetic-severe combined immunodeficient mouse model. BMI-1 prevents stem cell aging, at least partly, by blocking expression of the cyclin-dependent kinase inhibitor p16(Ink4a), dysregulation of the Bmi-1/p16(Ink4a) pathway provokes an aging-associated decline of submandibular gland function.

BMI-1 inhibitor PTC596 downregulates MCL-1 and induces p53-independent mitochondrial apoptosis in acute myeloid leukemia progenitor cells, PTC-209 also exhibits synergistic and additive anti-myeloma activity when combined with other epigenetic inhibitors targeting EZH2 and BET bromodomains.

 

 

References:

1. Douglas D, et al. BMI-1 promotes ewing sarcoma tumorigenicity independent of CDKN2A repression. Cancer Res. 2008 Aug 15;68(16):6507-15.

2. Liu S, et al. Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells. Cancer Res. 2006 Jun 15;66(12):6063-71.

3. Yamakoshi K, et al. Dysregulation of the Bmi-1/p16(Ink⁴a) pathway provokes an aging-associated decline of submandibular gland function. Aging Cell. 2015 Aug;14(4):616-24.

4. Nishida Y, et al. The novel BMI-1 inhibitor PTC596 downregulates MCL-1 and induces p53-independent mitochondrial apoptosis in acute myeloid leukemia progenitor cells. Blood Cancer J. 2017 Feb 17;7(2):e527.

5. Alzrigat M, et al. The polycomb group protein BMI-1 inhibitor PTC-209 is a potent anti-myeloma agent alone or in combination with epigenetic inhibitors targeting EZH2 and the BET bromodomains. Oncotarget. 2017 Oct 20;8(61):103731-103743.

 

Cat. No. Product Name CAS No. Information
PC-60464

PTC-028

1782970-28-8

PTC-028 (PTC028) is a novel potent, selective, orally bioavailable BMI-1 inhibitor with potent anti-MM activity against primary MM cells (IC50=10-100 nM); decreases BMI-1 levels by posttranslational modification, selectively inhibits cancer cells in clonal growth and viability assays (IC50=100 nM), without effeccts on normal cells; exhibits significant antitumor activity in mouse model of ovarian cancer.

PC-61790

RU-A1

315704-70-2 RU-A1 is a novel potent BMI1 inhibitor that targets cellular self-renewal in hepatocellular carcinoma (HCC); downregulates BMI1 expression, impaires cell viability, reduces cell migration, and sensitizes HCC cells to 5-FU in vitro; effectively reduces cancer stem-like cells (CSCs) content, and abrogates tumor growth in vivo in zebrafish.
PC-60486

PTC-596

A novel, orally active, small molecule inhibitor of BMI-1 that accelerates BMI-1 degradation, inhibits AML cells growth with IC50 of <100 nM; reduces total BMI-1 protein levels by 87% and 61% in MOLM-13 and OCI-AML3 cells at 100 nM, induces apoptosis and reduces the levels of ubiquitylated histone H2A; downregulates MCL-1 and induces p53-independent mitochondrial apoptosis in acute myeloid leukemia progenitor cells.

Ovarian Cancer

Phase 1 Clinical

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