Abstract 3883: Pharmacologic profile of the oral novel pan-CDK inhibitor BAY 1000394 in chemosensitive and chemorefractory tumor models
Authors: Siemeister Gerhard , Lücking Ulrich , Wengner Antje , Lienau Philip , Schatz Christoph , Mumberg Dominik , Ziegelbauer Karl 
Published: February 2011

We report on the pharmacological profile of the novel pan-CDK inhibitor BAY 1000394. Loss of cell cycle control and increased resistance to apoptosis represent major hallmarks of cancer. Cyclin-dependent kinases (CDKs) belong to a family of serine/threonine kinases which associate with an activating cyclin regulatory subunit. Cell cycle CDKs 1, 2, 4 & 6 are required for the correct timing and order of the events of the cell division cycle, whereas non-cell cycle CDKs 7 and 9 have been shown to be involved in gene transcription via regulation of RNA polymerase II activity. Deregulated CDK activity results in loss of cell cycle checkpoint function and increased expression of anti-apoptotic proteins, which has been directly linked to the molecular pathology of cancer. BAY 1000394 is a nanomolar pan CDK inhibitor (IC50s: CDK1/CycB, 7 nM; CDK2/CycE, 9 nM; CDK4/CycD1, 11 nM; CDK9/CycT1, &lt;10 nM). This inhibitor shows a broad spectrum profile of cell proliferation inhibition carried out in a panel of 26 human tumor cell lines with a mean IC50 of 16 nM (8-37 nM). The cellular activity of BAY 1000394 was independent of the presence of functional p53 or retinoblastoma (Rb) tumor suppressor proteins. BAY 1000394 induced disappearance of the hyperphosphorylated form of Rb protein in MCF7 and HCT116 tumor cells indicating intracellular inhibition of CDK2 and CDK4. Furthermore, the compound inhibited the phosphorylation of the mitotic CDK1 substrate protein nucleophosmin in HeLa cells. Cell cycle profiles of BAY 1000394 treated HeLa cells were consistent with inhibition of CDK 1, 2 and 4 as demonstrated in cell cycle block and release experiments. A robust decrease of viability of non-proliferating peripheral blood mononuclear cells isolated from a B-CLL patient (EC50: 15 nM) was observed and indicated inhibition of intracellular CDK9. Oral dosing of BAY 1000394 at various schedules (QD or BID x 2 and 5 days off) potently inhibited growth of human cervical HeLa-MaTu xenograft tumors in a dose-dependent manner. The MTD for BAY 1000394 was found to be 2.0 mg/kg on QD schedule and 2.5 mg/kg on a BID intermittent schedule. At these two doses and schedules tumor growth inhibition (TGI) of 104% and 106% was achieved in this model. A single oral dose of 2.0 mg/kg of BAY 1000394 resulted in complete suppression of the hyperphosphorylated form of Rb protein in HeLa-MaTu tumor tissue for at least 7 hrs. BAY 1000394 was also highly efficacious in a paclitaxel-refractory HeLa-MaTu-ADR Res xenograft model, and in a cisplatin-refractory A2780-Cis human ovarian xenograft model. Furthermore, the growth of human colorectal HCT116 tumors in nude rats treated on once daily (QD) or on intermittent (BID x 2 and 5 days off) schedules was strongly inhibited (TGI of 85 - 88%). In conclusion, BAY 1000394 is a highly potent oral pan-CDK inhibitor with a pharmacological profile suggesting activity in a broad range of histological tumor subtypes.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3883.