Ibulocydine

Ibulocydine is an isobutyrate prodrug of the Cdk inhibitor BMK-Y101, with oral activity, and exhibits IC₅₀ values of approximately 50 nM against CDK1/CDK2, 530 nM against CDK7/cyclin H/Mat1, and 85 nM against CDK9/cyclin T. Ibulocydine reduces the phosphorylation levels of Rb, nucleolin, and RNA polymerase II CTD Ser-5 and Ser-2, downregulates the expression of Mcl-1, survivin, and XIAP, decreases MMP-9 expression, and lowers the Bcl-2/Bax ratio, activates calpain-mediated Bax cleavage, cytochrome c release, and caspase activation. Ibulocydine induces apoptosis, inhibits the growth of cancer cells and xenografts, enhances the sensitivity of cancer cells to TRAIL and radiotherapy, and blocks cancer cell metastasis. Ibulocydine can be used in research related to various cancers, including hepatocellular carcinoma, triple-negative breast cancer, lung cancer, and colon cancer^[1][2][3][4]. In Vitro:Ibulocydine (0-50 μM; 18-24 h) dose-dependently inhibits the viability of SK-HEP-1, HepG2, and SNU-354 cells and suppresses DNA synthesis in SNU-354 cells^[1].
Ibulocydine (0.1-50 μM; 24 h) inhibits Cdk7-mediated RNA polymerase II Ser-5 phosphorylation and Cdk9-mediated RNA polymerase II Ser-2 phosphorylation in SNU-354, SK-HEP-1, and HepG2 cells; the corresponding IC₅₀ values in SNU-354 cells are 0.45 μM and 0.33 μM, respectively, with minimal effects on total RNA polymerase II levels^[1].
Ibulocydine (50 μM; 6-12 h) inhibits Cdk1-mediated nucleolin phosphorylation by approximately 50% within 12 h and suppresses Cdk2-mediated Rb phosphorylation by about 50% within 6 h in human hepatocellular carcinoma SNU-354 cells^[1].
Ibulocydine (10 μM; 6-24 h) time-dependently reduces the mRNA and protein levels of Mcl-1, survivin, and XIAP in SNU-354, SK-HEP-1, and HepG2 cells^[1].
Ibulocydine (50 μM; 6 h) induces PARP cleavage (a marker of apoptosis) in SNU-354, SK-HEP-1, and HepG2 cells^[1].
Ibulocydine (0.1-50 μM; 24 h) dose-dependently activates caspase-3 activity in SNU-354 cells^[1].
Ibulocydine (10-50 μM; 12 h) increases the sub-G₁ apoptotic cell population in SNU-354, SK-HEP-1, and HepG2 cells in a dose- and time-dependent manner, but has no effect on the sub-G₁ cell population in normal mouse hepatocytes AML-12^[1].
Ibulocydine (24 h) reduces the viability of Hs578T, MDA-MB-231-Luc, and MDA-MB-435S cells in a dose-dependent manner, with IC₅₀ values of 3.07 μM, 4.64 μM, and 3.25 μM, respectively^[2].
Ibulocydine (1-3 μM; 12 h exposure followed by 9 days of incubation) inhibits long-term colony formation in Hs578T, MDA-MB-231-Luc, and MDA-MB-435S cells^[2].
Ibulocydine (0.25-3 μM; 24 h) induces dose-dependent increases in cleaved caspase-3 and cleaved PARP in Hs578T, MDA-MB-231-Luc, and MDA-MB-435S cells, and decreases the expression of anti-apoptotic proteins XIAP, Bcl-xL, survivin, and Mcl-1, as well as dose-dependent reductions in the protein levels of MMP-2, MMP-9, Snail 1/2, TWIST, and ZEB1^[2].
Ibulocydine (3 μM; 24 h) induces apoptotic cell death in Hs578T, MDA-MB-231-Luc, and MDA-MB-435S cells^[2].
Ibulocydine (50-100 nM; 24 h) sensitizes TRAIL-resistant human hepatocellular carcinoma cells Hep3B and SK-Hep1 to TRAIL-induced caspase-dependent apoptosis, and synergistic cell death is observed upon combined treatment^[3].
Ibulocydine (0.05 μM) inhibits Cdk7/Cdk9 activity in Hep3B cells, and co-treatment with TRAIL induces apoptosis in Hep3B and SK-Hep1 cells through calpain-mediated Bax cleavage^[3].
Ibulocydine (50-100 nM; 24 h) enhances the sensitivity of human hepatocellular carcinoma cells Hep3B and SK-Hep1 to TRAIL through calpain activation, which mediates Bax cleavage and subsequent caspase-dependent apoptosis^[3].
Combined treatment with ibulocydine (50 nM; 24 h) and TRAIL induces apoptosis in human hepatoma Hep3B cells overexpressing Bcl-xL, and this effect is not blocked by Bcl-xL overexpression^[3].
Ibulocydine (0.4-0.8 μM, 30 min followed by 10 Gy radiotherapy, with a total incubation time of 24 h) induces caspase-dependent apoptosis in human lung cancer A549 cells and human colon cancer RKO cells through the cleavage of caspase-3, caspase-9, and PARP^[4].
Ibulocydine (0.1-1 μM; 16-24 h) inhibits RNA polymerase II phosphorylation at Ser-2 and Ser-5 sites and regulates Bcl-2 and Bax expression at the transcriptional level in a dose-dependent manner; in human lung cancer A549 cells and human colon cancer RKO cells, its combination with radiotherapy reduces the Bcl-2/Bax ratio^[4].
Ibulocydine (1-3 μM; 24 h) inhibits the migration of Hs578T and MDA-MB-231-Luc cells in a dose-dependent manner; at (0.5-1 μM), it inhibits the migration of MDA-MB-435S cells^[2].
Ibulocydine (0.5-1 μM; 24 h) inhibits the invasion of Hs578T, MDA-MB-231-Luc, and MDA-MB-435S cells in a dose-dependent manner^[2].
Combined treatment with ibulocydine (50-100 nM; 24 h) and TRAIL induces apoptosis in Hep3B and SK-Hep1 human hepatocellular carcinoma cells through mitochondrial translocation of cleaved Bax, which mediates MMP loss and cytochrome c release^[3].
Ibulocydine (0.4-0.8 μM; pretreatment for 30 min before 10 Gy radiotherapy, with a total incubation time of 24 h) induces significant mitochondrial dysfunction in human lung cancer A549 cells and human colon cancer RKO cells, including MMP loss and cytochrome c release, and its effect depends on the downregulation of Bcl-2 expression levels^[4].
Ibulocydine (24 h) synergizes with radiotherapy to reduce the viability of A549, RKO, Hep3B, and MCF-7 cells; among these, the viability inhibitory effect begins at 1 μM in A549 cells and at concentrations above 0.8 μM in RKO cells^[4].
Ibulocydine (0.4-0.8 μM; pretreatment for 30 min before 10 Gy radiotherapy, with a total incubation time of 24 h) increases sub-G1 cell accumulation in human lung cancer A549 cells and human colon cancer RKO cells^[4]. In Vivo:Ibulocydine (4-20 mg/kg; i.p.; 5 times per week; for 3 weeks) inhibits the growth of hepatocellular carcinoma xenografts in nude mice; it also induces tumor cell apoptosis in a dose-dependent manner, with no toxicity detected in normal liver tissue^[1].
Ibulocydine (100 μg per mouse; intrathecal injection; once every 3 days for a total of 3 doses) combined with radiotherapy significantly delays tumor growth in A549 xenograft mice, accompanied by decreased Bcl-2 expression, without causing body weight loss^[4].
Ibulocydine (3 µM; in vitro pretreatment; 6 h) inhibits lung metastasis of triple-negative breast cancer cells in a mouse model, as evidenced by persistently lower total flux of luciferase at day 56 and reduced tumor burden in the lungs^[2].