Gerd Rühter

Identification of Atuveciclib (BAY 1143572), the First Highly Selective, Clinical PTEFb/CDK9 Inhibitor for the Treatment of Cancer

Selective inhibition of exclusively transcription‐regulating PTEFb/CDK9 is a promising new approach in cancer therapy. Starting from lead compound BAY‐958, lead optimization efforts strictly focusing on kinase selectivity, physicochemical and DMPK properties finally led to the identification of the orally available clinical candidate atuveciclib (BAY 1143572). Structurally characterized by an unusual benzyl sulfoximine group, BAY 1143572 exhibited the best overall profile in vitro and in vivo, including high efficacy and good tolerability in xenograft models in mice and rats. BAY 1143572 is the first potent and highly selective PTEFb/CDK9 inhibitor to enter clinical trials for the treatment of cancer.

Abstract 4538: BAY 1112054, a highly selective, potent and orally available inhibitor of PTEFb/CDK9, shows convincing anti-tumor activity

The family of cyclin-dependent kinase (CDK) proteins consists of multiple cell cycle regulating CDK members as well as members involved in the regulation of gene transcription like CDK9/PTEFb (positive transcription elongation factor b). Inhibition of PTEFb and its direct downstream target RNA polymerase II is thought to cause rapid depletion of short-lived mRNA transcripts of important survival proteins like c-myc and Mcl-1 and thereby to induce growth delay and apoptosis in addicted tumor cells. In contrast to pan-CDK inhibitiors which are currently evaluated in Phase I and II clinical trials, PTEFb selective inhibitors have not been explored for clinical utility. BAY 1112054 is a potent and highly selective PTEFb-kinase inhibitor with low nanomolar activity against PTEFb/CDK9 and an at least 50-fold selectivity against other CDKs in enzymatic assays. Furthermore, BAY 1112054 shows a favourable selectivity against non-CDK kinases in vitro. The compound exhibits broad anti-proliferative activity against a panel of tumor cell lines with sub-micromolar IC-50 values. In line with the proposed mode of action, a concentration-dependent inhibition of the phosphorylation of the RNA polymerase II was observed in A549 tumor cells. This inhibition was accompanied by a reduction of intracellular Mcl-1 protein levels. Furthermore, BAY 1112054 increased DNA fragmentation in synchronized HeLa cells upon compound treatment for 24 hours. BAY 1112054 showed convincing in vivo efficacy at tolerated doses in two xenograft models in mice. Once daily oral treatment led to complete tumor stasis in established MOLM-13 AML xenografts. Pharmacokinetic analysis revealed that unbound plasma levels were 8 to 12 hours above the cellular IC50 in this model. In vivo efficacy and tolerability of the once daily po schedule of BAY 1112054 was confirmed in NCI-H82 SCLC xenografts. Xenografted tumors of this model showed lower levels of RNA polymerase II phosphorylation and Mcl-1 upon treatment with BAY 1112054. In conclusion, our data provides in vitro and in vivo proof of concept for BAY 1112054, a potent and highly selective inhibitor of PTEFb/CDK9 with first-in-class potential, and warrant further clinical evaluation of PTEFb selective inhibitors for the treatment of cancers addicted to the transcription of short-lived anti-apoptotic survival proteins. Citation Format: Arne Scholz, Ulrich Lucking, Gerhard Siemeister, Philip Lienau, Knut Eis, Antje Wengner, Kirstin Petersen, Ulf Bomer, Peter Nussbaumer, Axel Choidas, Gerd Ruhter, Jan Eickhoff, Carsten Schultz-Fademrecht, Bert Klebl, Stuart Ince, Franz von Nussbaum, Dominik Mumberg, Michael Brands, Karl Ziegelbauer. BAY 1112054, a highly selective, potent and orally available inhibitor of PTEFb/CDK9, shows convincing anti-tumor activity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4538. doi:10.1158/1538-7445.AM2014-4538