Apelin-13 is an endogenous peptidic agonist of the apelin receptor (APJ) receptor with the potential for improving cardiac function in heart failure patients. However, the low plasma stability of apelin-13 necessitates continuous intravenous infusion for therapeutic use. There are several approaches to increase the stability of apelin-13 including attachment of pharmacokinetic enhancing groups, stabilized peptides, and Fc-fusion approaches. We sought a small-molecule APJ receptor agonist approach to target a compound with a pharmacokinetic profile amenable for chronic oral administration. This manuscript describes sequential optimization of the pyrimidinone series, leading to pyridinone 14, with in vitro potency equivalent to the endogenous ligand apelin-13 and with an excellent oral bioavailability and PK profile in multiple preclinical species. Compound 14 exhibited robust pharmacodynamic effects similar to apelin-13 in an acute rat pressure-volume loop model and was advanced as a clinical candidate.

Endothelial lipase (EL) hydrolyzes phospholipids in high-density lipoprotein (HDL) resulting in reduction in plasma HDL levels. Studies with murine transgenic, KO, or loss-of-function variants strongly suggest that inhibition of EL will lead to sustained plasma high-density lipoprotein cholesterol (HDL-C) increase and, potentially, a reduced cardiovascular disease (CVD) risk. Herein, we describe the discovery of a series of oxadiazole ketones, which upon optimization, led to the identification of compound 12. Compound 12 was evaluated in a mouse pharmacodynamics (PD) model and demonstrated a 56% increase in plasma HDL-C. In a mouse reverse cholesterol transport study, compound 12 stimulated cholesterol efflux by 53% demonstrating HDL-C functionality.

A low level of high density lipoprotein (HDL) is an independent risk factor for cardiovascular disease. HDL reduces inflammation and plays a central role in reverse cholesterol transport, where cholesterol is removed from peripheral tissues and atherosclerotic plaque. One approach to increase plasma HDL is through inhibition of endothelial lipase (EL). EL hydrolyzes phospholipids in HDL resulting in reduction of plasma HDL. A series of benzothiazole sulfone amides was optimized for EL inhibition potency, lipase selectivity and improved pharmacokinetic profile leading to the identification of Compound 32. Compound 32 was evaluated in a mouse pharmacodynamic model and found to show no effect on HDL cholesterol level despite achieving targeted plasma exposure (C-trough > 15 fold over mouse plasma EL IC50 over 4 days).

An oxidative intermolecular enolate heterocoupling reaction was employed for the synthesis of anti-2,3-disubstituted succinic acid mono- and differentially protected diesters. Tactical approaches to access all the diastereomers are discussed. The method was applied to the synthesis of a potent anticancer agent, BMS-906024.

Abstract CK2 is a highly conserved, and constitutively active family of serine/threonine kinases abnormally elevated in a wide variety of cancers and linked to poor prognosis and disease progression. The enzymes form as hetero-tetrameric complexes comprised of two highly related catalytic subunits (α or α´) with two regulatory β subunits in various combinations and distributions, depending on cell type. While CK2 plays a role in normal growth and development, deregulation of the enzymes has been shown to promote and maintain a malignant phenotype through mechanisms in both the anti-apoptotic and the pro-proliferative signaling pathways. CK2 has been reported to modulate the activity of several oncogenic transcription factors including CREB, Myc, Jun and Fos. Studies with RNAi and small molecule compounds have demonstrated tumor cell dependence on CK2. We sought to identify potent CK2 inhibitors to probe the function of CK2 in cancer-linked pathways and for evaluation in CK2 dependent tumor xenograft models. Herein we report SAR studies in the imidazo[1,2-b]pyridazine chemotype leading to the discovery of BMS-595, a highly potent and selective ATP-competitive CK2 inhibitor with a commensurate level of cellular potency. BMS-595 demonstrates strong PK/PD correlations and robust, oral anti-tumor efficacy in CK2-driven xenograft models at tolerated doses. Citation Format: Christine M. Tarby, Liqi He, Brian E. Fink, Andrew Nation, Yufen Zhao, Soong-Hoon Kim, Libing Chen, John S. Tokarski, Chiang Yu, Jonathan G. Pabalan, Urvashi V. Roongta, Jonathan Lippy, Mary Obermeier, Paul A. Elzinga, Aberra Fura, Benjamin Henley, Joseph J. Fargnoli, William R. Foster, Ashvinikumar V. Gavai, Tai W. Wong, John T. Hunt, Gregory D. Vite, Ashok V. Purandare, Brent A. Rupnow. The identification of BMS-595, an orally active imidazo[1,2-b]pyridazine CK2 inhibitor with in vivo anti-tumor activity. [abstract]. In: 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 5417. doi:10.1158/1538-7445.AM2015-5417

Abstract Deregulation of the Notch pathway has been shown to be oncogenic in numerous tissue types including T-cell acute lymphoblastic leukemia (T-ALL), breast cancer, non-small cell lung cancer, and colorectal carcinoma. Notch signal activation can cause uncontrolled proliferation, restrict differentiation leading to increased self-renewal capacity, evasion of apoptosis, and enhancement of angiogenesis and metastasis. There is increasing evidence that Notch plays a role in the maintenance and survival of cancer stem cells. γ-Secretase mediates the Notch signaling pathway by releasing the Notch intracellular domain (NICD) which translocates to the nucleus and binds to the transcription factor CSL to activate transcription of various target genes. BMS-906024 is a potent pan-Notch inhibitor that demonstrated robust anti-tumor activity at tolerated doses in multiple tumor xenograft models. It is being evaluated in Phase 1 clinical studies. BMS-906024 is being administered IV (once weekly) in the clinic and the projected human efficacious dose is 4 - 6 mg. Based on the preclinical data, the projected human half-life of BMS-906024 is in the 37 h - 124 h range. This presentation will describe further structure-activity relationships in the 1,4-benzodiazepinone series that culminated in the identification of BMS-983970 as an oral-pan-Notch inhibitor. Pharmacokinetic properties and in vivo evaluation of BMS-983970 in T-ALL and solid tumor xenograft models will be presented. Citation Format: Ashvinikumar V. Gavai, Yufen Zhao, Daniel O'Malley, Brian Fink, Claude Quesnelle, Derek Norris, Libing Chen, Soong-Hoon Kim, Wen-Ching Han, Patrice Gill, Weifang Shan, Aaron Balog, Andrew Tebben, Richard Rampulla, Dauh-Rurng Wu, Yingru Zhang, Arvind Mathur, Haiqing Wang, Zheng Yang, Qian Ruan, Robin Moore, David Rodrigues, Asoka Ranasinghe, Celia D'Arienzo, Ching Kim Tye, Ching Su, Gerry Everlof, Melissa Yarde, Mary Ellen Cvijic, Krista Menard, Mei-Li Wen, George Trainor, Bruce Fischer, John Hunt, Gregory Vite, Richard Westhouse, Francis Lee. BMS-983970, an oral pan-Notch inhibitor for the treatment of cancer. [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 1643. doi:10.1158/1538-7445.AM2014-1643

The design, synthesis and characterization of a phosphonate inhibitor of N-acetylneuraminate-9-phosphate phosphatase (HDHD4) is described. Compound 3, where the substrate C-9 oxygen was replaced with a nonlabile CH2 group, inhibits HDHD4 with a binding affinity (IC50 11 μM) in the range of the native substrate Neu5Ac-9-P (compound 1, Km 47 μM). Combined SAR, modeling and NMR studies are consistent with the phosphonate group in inhibitor 3 forming a stable complex with native Mg2+. In addition to this key interaction, the C-1 carboxylate of the sugar interacts with a cluster of basic residues, K141, R104 and R72. Comparative NMR studies of compounds 3 and 1 with Ca2+ and Mg2+ are indicative of a highly dynamic process in the active site for the HDHD4/Mg2+/3 complex. Possible explanations for this observation are discussed.

Casein kinase 2 (CK2) is a serine/threonine kinase that has been implicated in the regulation of a number of oncogenic or tumor suppressor proteins. CK2 activity has been shown to be elevated in numerous studies in a variety of cancer types. CK2 has been shown to phosphorylate numerous cellular proteins. Among the proteins regulated directly or indirectly by CK2 phosphorylation are oncogenes and tumor suppressor proteins including beta-catenin, c-Myc, PML, and PTEN as well as proteins directly involved in cell cycle, apoptosis, and transcriptional regulation. The plethora of CK2 substrates and their participation in various cellular processes is a major confounding factor in understanding the role of CK2 in oncogenesis. Unlike other kinase targets that participate in relatively linear growth factor signaling pathways, CK2 appears to function more “laterally,” across many important signaling pathways to promote growth and survival of cancer cells. It is clear from numerous studies using siRNA as well as small molecule CK2 inhibitors that cancer cells are highly dependent upon CK2 for growth and survival. As a result, new small molecule inhibitors of CK2 may provide useful tools for probing CK2 biology and may also provide therapeutic benefits against several cancer types. Herein, we report our efforts toward the identification of CK2 inhibitors based on an imidazopyridazine carbonitrile scaffold. Lead compounds from this series demonstrate low nanomolar CK2 biochemical potency, while achieving excellent selectivity versus the majority of kinases in the human kinome. The development of structure-activity relationships and the establishment of a strong correlation between biochemical potency, inhibition of cellular protein target phosphorylation and anti-proliferative effects in targeted cancer cell lines will be presented. In addition, the optimization of pharmacokinetic properties resulting in compounds with excellent in vivo exposure has allowed for the investigation of CK2 inhibition in a pharmacodynamic model. Finally, our efforts to elucidate pathway effects mediated by CK2 in model colon cancer cell lines, including gene expression profiling using advanced small molecules leads, will be disclosed. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B284. Citation Format: Brian Fink, Ashvinikumar Gavai, Soong-Hoon Kim, Yufen Zhao, Ashok Purandare, Gregory Vite, John Tokarski, Chiang Yu, Benjamin Henley, Joseph Fargnoli, Heshani Desilva, Petra Ross-MacDonald, Brent Rupnow, Tai W. Wong. Discovery of imidazopyridazinecarbonitriles as potent, selective inhibitors of CK2. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B284.