Protein kinases are highly tractable targets for drug discovery. However, the biological function and therapeutic potential of the majority of the 500+ human protein kinases remains unknown. We have developed physical and virtual collections of small molecule inhibitors, which we call chemogenomic sets, that are designed to inhibit the catalytic function of almost half the human protein kinases. In this manuscript we share our progress towards generation of a comprehensive kinase chemogenomic set (KCGS), release kinome profiling data of a large inhibitor set (Published Kinase Inhibitor Set 2 (PKIS2)), and outline a process through which the community can openly collaborate to create a KCGS that probes the full complement of human protein kinases.

Protein kinases are highly tractable targets for drug discovery. However, the biological function and therapeutic potential of the majority of the 500+ human protein kinases remains unknown. We have developed physical and virtual collections of small molecule inhibitors, which we call chemogenomic sets, that are designed to inhibit the catalytic function of almost half the human protein kinases. In this manuscript we share our progress towards generation of a comprehensive kinase chemogenomic set (KCGS), release kinome profiling data of a large inhibitor set (Published Kinase Inhibitor Set 2 (PKIS2)), and outline a process through which the community can openly collaborate to create a KCGS that probes the full complement of human protein kinases.

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PTEFb/CDK9 mediated transcription of short-lived anti-apoptotic survival proteins like Mcl-1 and Myc plays a critical role in cancer cell growth and survival in various tumor entities including AML. In addition, these survival proteins play important roles in the development of resistance to chemotherapy. We previously disclosed the preclinical profile of BAY 1143572, the first selective, orally available PTEFb/CDK9 inhibitor that entered clinical development [1-3]. BAY 1143572 had low nanomolar activity against PTEFb/CDK9, an at least 50-fold selectivity against other CDKs in enzymatic assays and broad anti-proliferative activity against a panel of tumour cell lines with sub-micromolar IC50 values. BAY 1143572 also showed single agent in vivo efficacy at tolerated doses in various xenograft tumour models in mice and rats upon once daily oral administration. To fully explore future treatment options using selective PTEFb/CDK9 inhibitors we initiated a follow-up program to identify novel PTEFb/CDK9 inhibitors for treatment of cancer with increased potency enabling i.v. treatment of patients. Extensive lead optimisation efforts, including various scaffold hops, led to the identification of BAY 1251152. In comparison to oral BAY 1143572, BAY 1251152 shows significantly increased biochemical (IC50 CDK9 = 3 nM) and cellular potency (IC50 MOLM13 = 29 nM), increased selectivity against CDK2 as well as high permeability and no efflux. The significantly reduced therapeutic dose and high solubility of BAY 1251152 enable the desired i.v. application. BAY 1251152 demonstrated excellent efficacy upon i.v. treatment in xenograft models (e.g. MOLM13) in mice and rats. BAY 1251152 is currently being evaluated in Phase I studies (NCT02635672; NCT02745743) to determine the safety, tolerability, pharmacokinetics and initial pharmacodynamic biomarker response in patients with advanced cancer. This presentation will highlight the key learnings from our PTEFb/CDK9 i.v. lead optimization program and disclose the structure of BAY 1251152 for the first time. [1]: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3022. [2]: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr DDT02-02. doi:10.1158/1538-7445.AM2015-DDT02-02. [3]: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2828. doi:10.1158/1538-7445.AM2015-2828 Citation Format: Ulrich T. Luecking, Arne Scholz, Dirk Kosemund, Rolf Bohlmann, Hans Briem, Philip Lienau, Gerhard Siemeister, Ildiko Terebesi, Kirstin Meyer, Katja Prelle, Ray Valencia, Stuart Ince, Franz von Nussbaum, Dominik Mumberg, Karl Ziegelbauer, Michael Brands. Identification of potent and highly selective PTEFb inhibitor BAY 1251152 for the treatment of cancer: from p.o. to i.v. application via scaffold hops [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 984. doi:10.1158/1538-7445.AM2017-984

The integrity of the genome of eukaryotic cells is secured by complex signaling pathways, known as DNA damage response (DDR). Recognition of DNA damage activates DDR pathways resulting in cell cycle arrest, induction of DNA repair, or cell death. Proteins that directly recognize aberrant DNA structures recruit and activate kinases of the DDR pathway, such as ATR (ataxia telangiectasia and Rad3-related). ATR responds to a broad spectrum of DNA damage, including double-strand breaks (DSB) and lesions derived from interference with DNA replication as well as increased replication stress. Therefore, inhibition of ATR kinase activity could be the basis for a novel anti-cancer therapy in tumors with increased DNA damage, deficiency in DNA damage repair or replication stress. Radium-223 dichloride (Xofigo®) is the first and only approved targeted alpha therapy so far. It is indicated for the treatment of patients with castration-resistant prostate cancer (CRPC), symptomatic bone metastases and no known visceral metastatic disease, based on improvement of overall survival. It exhibits strong cytotoxic effects on adjacent cells via the induction of DNA DSB. Here, we disclose for the first time the structure and functional characterization of the novel ATR kinase inhibitor BAY 1895344. In vitro, BAY 1895344 is a selective low-nanomolar inhibitor of ATR kinase activity, potently inhibiting proliferation of a broad spectrum of human tumor cell lines (median IC50 of 78 nM). A clear separation between highly sensitive (IC50 <10 nM) and less sensitive cell lines was observed. The majority of the sensitive cell lines are characterized by mutations affecting the ATM (ataxia telangiectasia mutated) pathway. In cellular mechanistic assays BAY 1895344 inhibited hydroxyurea-induced H2AX phosphorylation demonstrating the anticipated mode of action. BAY 1895344 is an ATR inhibitor that exhibits strong in vivo anti-tumor efficacy in monotherapy in a variety of xenograft models of different indications that are characterized by DDR deficiencies, inducing stable disease in ovarian and colorectal cancer or even complete tumor remission in mantle cell lymphoma models. In addition, we could demonstrate that combination treatment with BAY 1895344 and Radium-223 exhibits clear synergistic anti-tumor activity in a bone metastases xenograft model of CRPC. Our findings validate the concept of synthetic lethality of genetically determined DNA repair deficiency and ATR blockade by demonstrating strong monotherapy efficacy of the highly potent ATR inhibitor BAY 1895344 in a variety of tumor indications. Furthermore, the mechanism-based combination potential of DNA damage induction by Radium-223 with BAY 1895344 creates a powerful new treatment option for CRPC patients with bone metastases. The start of clinical investigation of BAY 1895344 is planned early 2017. Citation Format: Antje Margret Wengner, Gerhard Siemeister, Ulrich Luecking, Julien Lefranc, Philip Lienau, Gesa Deeg, Eleni Lagkadinou, Li Liu, Sven Golfier, Christoph Schatz, Arne Scholz, Franz von Nussbaum, Michael Brands, Dominik Mumberg, Karl Ziegelbauer. ATR inhibitor BAY 1895344 shows potent anti-tumor efficacy in monotherapy and strong combination potential with the targeted alpha therapy Radium-223 dichloride in preclinical tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 836. doi:10.1158/1538-7445.AM2017-836