Vibha Oza

Discovery of a novel class of 2-ureido thiophene carboxamide checkpoint kinase inhibitors.

Checkpoint kinase-1 (Chk1, CHEK1) is a Ser/Thr protein kinase that mediates the cellular response to DNA-damage. A novel class of 2-ureido thiophene carboxamide urea (TCU) Chk1 inhibitors is described. Inhibitors in this chemotype were optimized for cellular potency and selectivity over Cdk1.

Synthesis and Evaluation of Triazolones as Checkpoint Kinase 1 Inhibitors.

Checkpoint kinase 1 (Chk1, CHEK1) is a Ser/Thr protein kinase that plays a key role in mediating the cellular response to DNA-damage. Synthesis and evaluation of a previously described class of Chk1 inhibitors, triazoloquinolones/triazolones (TZs) is further described herein. Our investigation of structure-activity relationships led to the identification of potent inhibitors 14c, 14h and 16e. Key challenges included modulation of physicochemical properties and pharmacokinetic (PK) parameters to enable compound testing in a Chk1 specific hollow fiber pharmacodynamic model. In this model, 16e was shown to abrogate topotecan-induced cell cycle arrest in a dose dependent manner. The demonstrated activity of TZs in this model in combination with a chemotherapeutic agent as well as radiotherapy validates this series of Chk1 inhibitors. X-ray crystal structures (PDB code: 2YEX and 2YER) for an initial lead and an optimized analog are also presented.

Discovery of a novel class of triazolones as checkpoint kinase inhibitors--hit to lead exploration.

Checkpoint Kinase-1 (Chk1, CHK1, CHEK1) is a Ser/Thr protein kinase that mediates cellular responses to DNA-damage. A novel class of Chk1 inhibitors, triazoloquinolones/triazolones (TZs) was identified by high throughput screening. The optimization of these hits to provide a lead series is described.

Discovery of heterocyclic sulfonamides as sphingosine 1-phosphate receptor 1 (S1P1) antagonists

We have discovered a novel class of heterocyclic sulfonamides that act as antagonists of the S1P1 receptor. While members of this series identified from a high-throughput screen showed promising levels of potency in a cell-based assay measuring the inhibition of receptor internalization, most compounds were excessively lipophilic and contained an oxidation-prone thioether moiety. As a result, such compounds suffered from poor physical properties and metabolic stability, limiting their utility as in vivo probes. By removing the thioether group and systematically developing an understanding of structure-activity relationships and the effects of lipophilicity on potency within this series, we have been able to identify potent compounds with vastly improved physical properties. A representative enantiopure triazole sulfonamide (33) has measurable bioavailability following a low (3mg/kg) oral dose in rat, highlighting an achievement of the early hit-to-lead efforts for this series.

Abstract B100: Structure-based design of AZ7732 a novel in vivo active beta-alanine-derived pan-IAP inhibitor.

Both monomeric and dimeric SMAC (Second Mitochondria-derived Activator of Caspaces) mimetics acting as IAP (Inhibitor of apoptosis proteins) anatgonists have been reported in the clinic as well as extensively in the literature (1). The first four amino acids in the N-terminal of SMAC (AVPI) are critical for binding to IAP proteins. Reported medicinal chemistry exploration of the AVPI template has primarily consisted of variation to the VPI position in the amino-terminal of the SMAC peptide. Structural illucidation of XIAP bound to IAP inhibitors has revealed a critical role for the alanine with dense hydrogen bonding, electrostatic and hydrophibic complementarity with the protein. To our knowledge, exploration of alanine modifications has been limited and generally led to significant reduction in potency. Using the molecular modeling software SuperStar(2), we investigated the publically available co-crystal structures of Smac-mimetics with cIAP1 and hypothesized that homologating the basic amine might be tolerated. Applying this strategy, we report on the successful transfer of a beta-alanine warhead to a number of monomeric scaffolds. The resulting novel monomers maintained cIAP1/2 potency albeit with a reduction in xIAP potency. We report here the first co-crystal structure of xIAP baculoviral IAP repeat 3 domain (BIR3) with a beta-alanine derived monomer. Examination of the binding site contacts in the co-crystal structure provided further insight into the optimization of the warhead. Herein we describe the synthesis, SAR and SPR of this novel warhead and the discovery of beta-alanine derived pan-IAP inhibitors. We show that the SAR can be transferred to dimers and is invariant to the position of dimerization. We report our efforts to optimize the series and mitigate Cyp3A4 inhibition. This work led to the discovery of AZ7732, a novel dimeric SMAC-mimetic; a pan inhibitor of IAPs (cIAP BIR3 IC50 = 12 nM, XIAP BIR3 IC50 = 13 nM, and XIAP BIR2 IC50 = 30 nM); potent in cells as a single agent (MDA-MB231 cIAP degradation IC50 = 0.2 nM, GI50 = 0.4 nM) and is synergistic in vitro in combination with gemcitabine. AZ7732 has favorable in vivo PK with physical properties suitable for IV dosing. AZ7732 is active in vivo as a single agent. Once weekly dosing in MDA-MB231 led to dose-dependent tumor growth inhibition with stasis achieved at 2.5 mpk, ¼ MTD. In conclusion, Structure-based design and medicinal chemistry efforts have successfully identified novel monomeric and dimeric SMAC mimetics leading to the discovery of a novel in vivo active dimeric pan-IAP inhibitor. (1) Fulda et al, Nat. Rev. Drug Disc., 11, 109-123, 2012. (2) M. L. Verdonk, et al, J. Mol. Biol., 289, 1093-1108, 1999 Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B100. Citation Format: Jamal C. Saeh, Brian Aquila, Daniel Russell, Edward Hennessy, Alex Hird, Melissa Vasbinder, Andrew Ferguson, Bin Yang, Maureen Hattersley, Naomi Laing, Terry MacIntyre, Troy Patterson, Galina Repik, Michael Rooney, Haiyun Wang, Dave Witson, Li Sha, Donald Cook, Paula Lewis, John Lee, Danyang Li, Victor Kamhi, Vibha Oza, Charles Omer. Structure-based design of AZ7732 a novel in vivo active beta-alanine-derived pan-IAP inhibitor. [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 B100.