[Show description][Hide description] DESCRIPTION: Abstract
A series of IAP antagonists based on an azabicyclooctane scaffold was designed and synthesized. The most potent of these compounds, 14b, binds to the XIAP BIR3 domain, the BIR domain of ML-IAP, and the BIR3 domain of c-IAP1 with K(i) values of 140, 38, and 33 nM, respectively. These compounds promote degradation of c-IAP1, activate caspases, and lead to decreased viability of breast cancer cells without affecting normal mammary epithelial cells. Finally, compound 14b inhibits tumor growth when dosed orally in a breast cancer xenograft model.
[Show abstract][Hide abstract] ABSTRACT: A-1155463, a highly potent and selective BCL-XL inhibitor, was discovered through nuclear magnetic resonance (NMR) fragment screening and structure-based design. This compound is substantially more potent against BCL-XL-dependent cell lines relative to our recently reported inhibitor, WEHI-539, while possessing none of its inherent pharmaceutical liabilities. A-1155463 caused a mechanism-based and reversible thrombocytopenia in mice and inhibited H146 small cell lung cancer xenograft tumor growth in vivo following multiple doses. A-1155463 thus represents an excellent tool molecule for studying BCL-XL biology as well as a productive lead structure for further optimization.
[Show abstract][Hide abstract] ABSTRACT: Because of the promise of BCL-2 antagonists in combating chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphoma (NHL), interest in additional selective antagonists of antiapoptotic proteins has grown. Beginning with a series of selective, potent BCL-XL antagonists containing an undesirable hydrazone functionality, in silico design and X-ray crystallography were utilized to develop alternative scaffolds that retained the selectivity and potency of the starting compounds.
[Show abstract][Hide abstract] ABSTRACT: Partnerships between industry and academia are becoming increasingly complex and relevant in the drive to discover innovative new medicines. We describe the structure of the collaboration between the University of California - San Francisco - Small Molecule Discovery Center (UCSF-SMDC) and Genentech to develop chemical matter that inhibits the activity of caspase-6. We focus on the scientific basis for the partnership and how the orientation-and transaction-related barriers were overcome. We describe the division of labor that allowed two groups to operate as a unified team to generate multiple chemical series with distinct mechanisms of action. The successful structure of the agreement serves as a model for future collaborations at both institutions.
No preview · Article · Feb 2014 · Current Topics in Medicinal Chemistry
[Show abstract][Hide abstract] ABSTRACT: Although they represent attractive therapeutic targets, caspases have so far proven recalcitrant to the development of drugs targeting the active site. Allosteric modulation of caspase activity is an alternate strategy that potentially avoids the need for anionic and electrophilic functionality present in most active-site inhibitors. Caspase-6 has been implicated in neurodegenerative disease, including Huntington's and Alzheimer's diseases. Herein we describe a fragment-based lead discovery effort focused on caspase-6 in its active and zymogen forms. Fragments were identified for procaspase-6 using surface plasmon resonance methods and subsequently shown by X-ray crystallography to bind a putative allosteric site at the dimer interface. A fragment-merging strategy was employed to produce nanomolar-affinity ligands that contact residues in the L2 loop at the dimer interface, significantly stabilizing procaspase-6. Because rearrangement of the L2 loop is required for caspase-6 activation, our results suggest a strategy for the allosteric control of caspase activation with drug-like small molecules.
[Show abstract][Hide abstract] ABSTRACT: Partnerships between industry and academia are becoming increasingly complex and relevant in the drive to discover innovative new medicines. We describe the structure of the collaboration between the University of California - San Francisco - Small Molecule Discovery Center (UCSF-SMDC) and Genentech to develop chemical matter that inhibits the activity of caspase-6. We focus on the scientific basis for the partnership and how the orientation- and transaction-related barriers were overcome. We describe the division of labor that allowed two groups to operate as a unified team to generate multiple chemical series with distinct mechanisms of action. The successful structure of the agreement serves as a model for future collaborations at both institutions.
Full-text · Article · Nov 2013 · Current topics in medicinal chemistry
[Show abstract][Hide abstract] ABSTRACT: The application of modeling and simulation techniques is increasingly common in preclinical stages of the drug development process. GDC-0917 [(S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-N-(2-(oxazol-2-yl)-4-phenylthiazol-5-yl)pyrrolidine-2-carboxamide] is a potent second generation antagonist of inhibitor of apoptosis (IAP) proteins being developed for the treatment of various cancers. GDC-0917 has low to moderate clearance in mouse (12.0 ml/min/kg), rat (27.0 mL/min/kg) and dog (15.3 mL/min/kg), and high clearance in monkey (67.6 mL/min/kg). Accordingly, oral bioavailability was lowest in monkey compared to other species. Based on our experience with a prototype molecule with similar structure, in vitro-in vivo extrapolation was used to predict a moderate clearance (11.5 mL/min/kg) in human. Predicted human volume of distribution was estimated using simple allometry at 6.69 L/kg. Translational pharmacokinetic-pharmacodynamic (PK-PD) analysis using results from MDA-MB-231-X1.1 breast cancer xenograft studies and predicted human pharmacokinetics suggests that ED50 and ED90 targets can be achieved in humans using acceptable doses (72 mg and 660 mg, respectively), and under an acceptable timeframe. The relationship between GDC-0917 concentrations and pharmacodynamic response (cIAP1 degradation) was characterized using an in vitro PBMC immunoassay. Simulations of human GDC-0917 plasma concentration-time profile and cIAP1 degradation at the 5 mg starting dose in the Phase 1 clinical trial agreed well with observations. This work shows the importance of leveraging information from prototype molecules, and illustrates how modeling and simulation can be used to add value to preclinical studies in the early stages of the drug development process.
Full-text · Article · Sep 2013 · Drug metabolism and disposition: the biological fate of chemicals
[Show abstract][Hide abstract] ABSTRACT: The prosurvival BCL-2 family protein BCL-XL is often overexpressed in solid tumors and renders malignant tumor cells resistant to anticancer therapeutics. Enhancing apoptotic responses by inhibiting BCL-XL will most likely have widespread utility in cancer treatment and, instead of inhibiting multiple prosurvival BCL-2 family members, a BCL-XL-selective inhibitor would be expected to minimize the toxicity to normal tissues. We describe the use of a high-throughput screen to discover a new series of small molecules targeting BCL-XL and their structure-guided development by medicinal chemistry. The optimized compound, WEHI-539 (7), has high affinity (subnanomolar) and selectivity for BCL-XL and potently kills cells by selectively antagonizing its prosurvival activity. WEHI-539 will be an invaluable tool for distinguishing the roles of BCL-XL from those of its prosurvival relatives, both in normal cells and notably in malignant tumor cells, many of which may prove to rely upon BCL-XL for their sustained growth.
Full-text · Article · Apr 2013 · Nature Chemical Biology
[Show abstract][Hide abstract] ABSTRACT: Inhibition of caspase-6 is a potential therapeutic strategy for some neurodegenerative diseases, but it has been difficult to develop selective inhibitors against caspases. We report the discovery and characterization of a potent inhibitor of caspase-6 that acts by an uncompetitive binding mode that is an unprecedented mechanism of inhibition against this target class. Biochemical assays demonstrate that, while exquisitely selective for caspase-6 over caspase-3 and -7, the compound's inhibitory activity is also dependent on the amino acid sequence and P1' character of the peptide substrate. The crystal structure of the ternary complex of caspase-6, substrate-mimetic and an 11 nM inhibitor reveals the molecular basis of inhibition. The general strategy to develop uncompetitive inhibitors together with the unique mechanism described herein provides a rationale for engineering caspase selectivity.
[Show abstract][Hide abstract] ABSTRACT: Inhibitor of apoptosis (IAP) proteins suppress apoptosis and are overexpressed in a variety of cancers. GDC-0152 is a potent and selective IAP antagonist being developed as an anti-cancer agent. In preclinical safety studies, dogs were particularly sensitive to GDC-0152 showing adverse signs of a TNF-α driven systemic inflammatory response, related to cIAP degradation and activation of NFκB signaling, at lower exposures compared to rat. In addition, downstream increases in systemic levels of cytokines and chemokines, such as monocyte chemotactic protein-1 (MCP-1), were observed. A semi-mechanistic population toxicokinetic/toxicodynamic (TK/TD) model incorporating transit compartments was used to fit MCP-1 plasma concentrations from rats or dogs given intravenous (iv) GDC-0152 doses. Estimated toxicodynamic (TD) parameters inferred that lower GDC-0152 plasma concentrations triggered more severe increases in plasma MCP-1 in dogs compared to rats. Human simulations performed using dog TD parameters and human pharmacokinetics predicted 300 to 2400% increases of MCP-1 in humans at iv doses from 0.76 to 1.48 mg/kg. Similar simulations using rat TD parameters suggest little or no change. Patients given intravenous doses of GDC-0152 up to 1.48 mg/kg iv showed no substantial increases in systemic MCP-1 or signs of a severe TNF-α driven systemic inflammatory response. Emerging clinical data reported for other IAP antagonists are consistent with our observations. Taken together, the data suggests dogs are more sensitive to IAP antagonists compared to humans and rats. This work illustrates how TK/TD analysis can be utilized to quantitatively translate and context an identified preclinical safety risk in dogs to humans
Full-text · Article · Oct 2012 · Toxicological Sciences
[Show abstract][Hide abstract] ABSTRACT: Inhibitor-of-apoptosis (IAP) proteins suppress apoptosis and are overexpressed in a variety of cancers. Small-molecule IAP antagonists are currently being tested in clinical trials as novel cancer therapeutics. GDC-0152 is a small-molecule drug that triggers tumor cell apoptosis by selectively antagonizing IAPs. GDC-0152 induces NF-κB transcriptional activity leading to expression of several chemokines and cytokines, of which tumor necrosis factor alpha (TNF-α) is the most important for single-agent tumor activity. TNF-α is a pleiotropic cytokine that drives a variety of cellular responses, comprising inflammation, proliferation, and cell survival or death depending on the cellular context. As malignant and normal cells produce TNF-α upon IAP antagonism, increased TNF-α could drive both efficacy and toxicity. The toxicity profile of GDC-0152 in dogs and rats was characterized after intravenous dose administration once every two weeks for four doses. Findings in both species consisted of a dose-related, acute, systemic inflammatory response and hepatic injury. Laboratory findings included elevated plasma cytokines, an inflammatory leukogram, and increased liver transaminases with histopathological findings of inflammatory infiltrates and apoptosis/necrosis in multiple tissues; a toxicology profile consistent with TNF-α-mediated toxicity. Dogs exhibited more severe findings than rats, and humans did not exhibit these findings, at comparable exposures across species. Furthermore, elevations in blood neutrophil count, serum MCP-1 and other markers of inflammation corresponded to GDC-0152 exposure and toxicity and thus may have utility as safety biomarkers.
[Show abstract][Hide abstract] ABSTRACT: A series of compounds were designed and synthesized as antagonists of cIAP1/2, ML-IAP, and XIAP based on the N-terminus, AVPI, of mature Smac. Compound 1 (GDC-0152) has the best profile of these compounds; it binds to the XIAP BIR3 domain, the BIR domain of ML-IAP, and the BIR3 domains of cIAP1 and cIAP2 with K(i) values of 28, 14, 17, and 43 nM, respectively. These compounds promote degradation of cIAP1, induce activation of caspase-3/7, and lead to decreased viability of breast cancer cells without affecting normal mammary epithelial cells. Compound 1 inhibits tumor growth when dosed orally in the MDA-MB-231 breast cancer xenograft model. Compound 1 was advanced to human clinical trials, and it exhibited linear pharmacokinetics over the dose range (0.049 to 1.48 mg/kg) tested. Mean plasma clearance in humans was 9 ± 3 mL/min/kg, and the volume of distribution was 0.6 ± 0.2 L/kg.
Full-text · Article · Mar 2012 · Journal of Medicinal Chemistry
[Show abstract][Hide abstract] ABSTRACT: ABT-737 and ABT-263 are potent inhibitors of the BH3 antiapoptotic proteins, Bcl-x(L) and Bcl-2. This class of putative anticancer agents invariantly contains an acylsulfonamide core. We have designed and synthesized a series of novel quinazoline-based inhibitors of Bcl-2 and Bcl-x(L) that contain a heterocyclic alternative to the acylsulfonamide. These compounds exhibit submicromolar, mechanism-based activity in human small-cell lung carcinoma cell lines in the presence of 10% human serum. This comprises the first successful demonstration of a quinazoline sulfonamide core serving as an effective benzoylsulfonamide bioisostere. Additionally, these novel quinazolines comprise only the second known class of Bcl-2 family protein inhibitors to induce mechanism-based cell death.
No preview · Article · Mar 2011 · Journal of Medicinal Chemistry
[Show abstract][Hide abstract] ABSTRACT: Preclinical Pharmacokinetic Assessment of GDC-0152, a Selective Antagonist of the Inhibitor of Apoptosis (IAP) Proteins
Hank La, Jason S Halladay, Young Shin, Susan Wong, Emile Plise, O. Helen Chan, John Flygare, Wayne Fairbrother, and Harvey Wong.
Genentech Inc., South San Francisco, CA.
Inhibitor of apoptosis (IAP) proteins are believed to suppress apoptosis and are overexpressed in a variety of cancers. GDC‑0152 is a potent and selective antagonist of the IAP proteins that was developed as a potential treatment of tumors that are resistant to chemotherapies or radiotherapy. The preclinical pharmacokinetics of GDC-0152 were investigated in mouse, rat, dog, and cynomolgus monkeys. Briefly, the compound was dosed intravenously (IV) at 1 mg/kg in mouse, rat, dog and monkey. In mouse, rat and monkey, plasma clearance was high (>80% of hepatic blood flow) at 72.0, 66.7, and 47.1 mL/min/kg, respectively. In dog, GDC-0152 had a moderate plasma clearance (52% of hepatic blood flow) of 16.2 mL/min/kg. In dose ranging studies, clearance was nonlinear in mouse and rat, but linear in dog and cynomolgus monkey. Estimates of volume of distribution were moderate in all species tested, ranging from 1.04 L/kg in dogs to 2.01 L/kg in rats. Mean half-life ranged from 0.427 hours in mice to 0.933 hours in dogs. Plasma protein binding was moderate (75%-92% bound) across species, except in rabbit where it was approximately 95% bound. Blood-plasma partition ratios ranged from 0.579 to 1.08 in all species tested suggesting that GDC-0152 does not preferentially distribute into red blood cells. Prediction of clearance in humans was performed using allometry and in vitro scaling using human hepatocytes. Both methodologies resulted in similar predicted human clearance values of 9.4 (allometry adjusted for maximum life potential) and 10 mL/min/kg (in vitro scaling using hepatocytes). Volume of distribution was predicted to be moderate at 1.2 L/kg in humans using allometry. Predicted half-life in humans was approximately 1.5 hours. Based upon the predicted pharmacokinetic profile in humans, this compound was advanced to human phase 1 clinical trials.
[Show abstract][Hide abstract] ABSTRACT: A series of IAP antagonists based on thiazole or benzothiazole amide isosteres was designed and synthesized. These compounds were tested for binding to the XIAP-BIR3 and ML-IAP BIR using a fluorescence polarization assay. The most potent of these compounds, 19a and 33b, were found to have K(i)'s of 20-30 nM against ML-IAP and 50-60 nM against XIAP-BIR3.
No preview · Article · Feb 2010 · Bioorganic & medicinal chemistry letters