The drug-target residence time model was first introduced in 2006 and has been broadly adopted across the chemical biology, biotechnology and pharmaceutical communities. While traditional in vitro methods view drug-target interactions exclusively in terms of equilibrium affinity, the residence time model takes into account the conformational dynamics of target macromolecules that affect drug binding and dissociation. The key tenet of this model is that the lifetime (or residence time) of the binary drug-target complex, and not the binding affinity per se, dictates much of the in vivo pharmacological activity. Here, this model is revisited and key applications of it over the past 10 years are highlighted.

The drug-target residence time model: a 10-year retrospective

Hsp90 is a highly abundant and ubiquitous molecular chaperone which plays an essential role in many cellular processes including cell cycle control, cell survival, hormone and other signalling pathways. It is important for the cell's response to stress and is a key player in maintaining cellular homeostasis. In the last ten years, it has become a major therapeutic target for cancer, and there has also been increasing interest in it as a therapeutic target in neurodegenerative disorders, and in the development of anti-virals and anti-protozoan infections. The focus of this review is the structural and mechanistic studies which have been performed in order to understand how this important chaperone acts on a wide variety of different proteins (its client proteins) and cellular processes. As with many of the other classes of molecular chaperone, Hsp90 has a critical ATPase activity, and ATP binding and hydrolysis known to modulate the conformational dynamics of the protein. It also uses a host of cochaperones which not only regulate the ATPase activity and conformational dynamics but which also mediate interactions with Hsp90 client proteins. The system is also regulated by post-translational modifications including phosphorylation and acetylation. This review discusses all these aspects of Hsp90 structure and function.

Hsp90: Structure and Function.

Therapies that target tumor metabolism represent a new horizon in anticancer therapies. In particular, cancer cells are dependent on the generation of lipids, which are essential for cell membrane synthesis, modification of proteins, and localization of many oncogenic signal transduction enzymes. Because fatty acids are the building blocks of these important lipids, fatty acid synthase (FASN) emerges as a unique oncologic target. FASN inhibitors are being studied preclinically and beginning to transition to first-in-human trials. Early generation FASN inhibitors have been studied preclinically but were limited by their pharmacologic properties and side-effect profiles. A new generation of molecules, including GSK2194069, JNJ-54302833, IPI-9119, and TVB-2640, are in development, but only TVB-2640 has moved into the clinic. FASN inhibition, either alone or in combination, holds promise as a novel therapeutic approach for patients with cancer.

https://clincancerres.aacrjournals.org/content/clincanres/21/24/5434.full.pdf

Molecular Pathways: Fatty Acid Synthase

Drug-target residence time (τ), one of the main determinants of drug efficacy, remains highly challenging to predict computationally and, therefore, is usually not considered in the early stages of drug design. Here, we present an efficient computational method, τ-random acceleration molecular dynamics (τRAMD), for the ranking of drug candidates by their residence time and obtaining insights into ligand-target dissociation mechanisms. We assessed τRAMD on a data set of 70 diverse drug-like ligands of the N-terminal domain of HSP90α, a pharmaceutically important target with a highly flexible binding site, obtaining computed relative residence times with an accuracy of about 2.3τ for 78% of the compounds and less than 2.0τ within congeneric series. Analysis of dissociation trajectories reveals features that affect ligand unbinding rates, including transient polar interactions and steric hindrance. These results suggest that τRAMD will be widely applicable as a computationally efficient aid to improving drug...

Estimation of Drug-Target Residence Times by tau-Random Acceleration Molecular Dynamics Simulations.

Dysregulation of cancer cell metabolism contributes to abnormal cell growth, the biological end point of cancer. We review here numerous affected oncogenes and metabolic pathways common in cancer and how they contribute to cancer pathogenesis and malignancy. This review also discusses various pharmacological manipulations that take advantage of these metabolic abnormalities and the current targeted therapies that have arisen from this research.

Cancer Metabolism: Current Understanding and Therapies

Hsp90 (Heat Shock Protein 90) Inhibitor Occupancy Is a Direct Determinant of Client Protein Degradation and Tumor Growth Arrest in Vivo

Fatty acid synthase (FASN) is a key enzyme responsible for fatty acids synthesis de novo in mammals. Overexpression of FASN is common in many cancers including prostate, breast and colon cancer and elevated expression of FASN has been linked with poor prognosis and reduced disease-free survival. Experiments with RNAi and small molecule inhibitors suggest that FASN is a metabolic oncogene with an important role in tumor growth and survival and an appealing target for cancer therapy. However, studies utilizing small molecule FASN inhibitors like orlistat and C75 have been confounded by the lack of potency and selectivity, as well as the poor pharmacological properties of these inhibitors. Herein we report pharmacological target validation studies of FASN using a potent, selective and orally bioavailable FASN inhibitor IPI-9119. Building on previous experience with serine hydrolase inhibitors, a series of novel mechanism-based FASN inhibitors were designed based on a tetrazolone carboxamide scaffold. Like orlistat, these analogs are irreversible inhibitors that specifically target the FASN thioesterase domain. Tetrazolone carboxamide analogs were shown to potently inhibit cellular FASN using an occupancy assay and to completely block de novo palmitate synthesis in HCT-116 colon cancer cells using a 13 C-glucose incorporation assay. Lead optimization of the tetrazolone carboxamide series resulted in the identification of IPI-9119 as a tool for in vivo proof-of-concept studies. IPI-9119 is a potent FASN inhibitor in both biochemical (IC 50 ∼1nM) and cellular occupancy assays (IC 50 ∼10nM), and shows more than 400-fold selectivity against several additional serine hydrolases. Importantly, IPI-9119 is orally bioavailable and has pharmacokinetic (PK) properties suitable for in vivo pharmacology studies. IPI-9119 was tested for growth inhibition in cancer cell lines in vitro and tumor xenograft models in vivo. Unexpectedly, in contrast to the knock-down studies and to data reported for orlistat and C75, IPI-9119 failed to elicit anti-proliferative effects in multiple cancer cell lines in vitro. Similarly, PK/PD experiments demonstrated that a single oral dose of IPI-9119 at 200 mg/kg leads to complete and sustained blockade of FASN in HCT-116 tumor xenografts, but IPI-9119 failed to show any anti-tumor activity when dosed as a single agent at 200 mg/kg BID for 10 days. In summary, we identified IPI-9119 as a potent, selective and orally bioavailable FASN inhibitor. Preliminary target validation studies with IPI-9119 in cancer cell lines and an HCT-116 xenograft model suggest that FASN inhibition alone is not sufficient to affect cancer cell proliferation and tumor growth. Further studies exploring combination treatments with IPI-9119 are warranted. Citation Format: Erin Brophy, James Conley, Patrick O9Hearn, Mark Douglas, Culver Cheung, John Coco, Laura D9Anello, Andrew Wylie, Thomas Tibbitts, Gregg Keaney, Lawrence Chan, Adilah Bahadoor, Dan Snyder, Marta Nevalainen, Alfredo Castro, Vito Palombella, Massimo Loda, Stephane Peluso. Pharmacological target validation studies of fatty acid synthase in carcinoma using the potent, selective and orally bioavailable inhibitor IPI-9119. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1891. doi:10.1158/1538-7445.AM2013-1891

Abstract 1891: Pharmacological target validation studies of fatty acid synthase in carcinoma using the potent, selective and orally bioavailable inhibitor IPI-9119.

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Hsp90 (Heat Shock Protein 90) Inhibitor Occupancy Is a Direct Determinant of Client Protein Degradation and Tumor Growth Arrest in Vivo

Abstract 1891: Pharmacological target validation studies of fatty acid synthase in carcinoma using the potent, selective and orally bioavailable inhibitor IPI-9119.