Pharmacological Promiscuity: Dependence on Compound Properties and Target Specificity in a Set of Recent Roche Compounds

Abstract

The term "pharmacological promiscuity" describes a compound's pharmacological activity at multiple targets. Pharmacological promiscuity is undesired in typical drug discovery projects, which focus on the "one drug-one target" paradigm. Off-target activity can lead to adverse drug reactions, or can obscure pharmacodynamic effects in animal models. Therefore, advanced lead compounds, pharmacological tool compounds, and drug candidates are usually screened against panels of safety-relevant targets to detect unwanted pharmacological activities. To identify determinants of pharmacological promiscuity, we compared the panel screening outcomes of 213 recent Roche compounds with their molecular properties. Pronounced promiscuity was not observed below a threshold Clog P value of 2. For basic compounds, the propensity for weak off-target activity was found to increase with calculated basicities, whereas the potential for strong off-target activity depends more qualitatively on the presence of a positive charge at physiological pH. Compounds originating from projects with an aminergic receptor or transporter as a therapeutic target are particularly prone to promiscuity; the promiscuity of such compounds is mainly caused by their activity at other aminergic targets in the screening panel.

Concise SAR Exploration Based on the “Head-to-Tail” Approach: Discovery of PI4KIIIα Inhibitors Bearing Diverse Scaffolds

“…17 In accordance with the previous results represented by 15 and 17, compound 20 having an ether moiety showed better potency; by a slight modification of the headgroup (22), the PI4KIIIα selectivity was further strengthened. Toward this end, we have successfully discovered a novel PI4KIIIα inhibitor having superb PI4KIIIα potency.…”

Nonproteasomal Targets of the Proteasome Inhibitors Bortezomib and Carfilzomib: a Link to Clinical Adverse Events

“…In some disease etiologies, targeting multiple proteins may improve the therapeutic efficacy, such as for antipsychotic drugs or kinase inhibitors with anticancer activity (1). However, off-target activity can lead to adverse drug reactions (ADR) such as the case with fenfluramine and torcetrapib, 2 agents halted in development because of fatal hypertension that was the consequence of secondary target inhibition (1)(2)(3). Highlighting the promiscuity of small molecule inhibitors, a recent in silico screening of 213 Roche compounds revealed an average of 6.3 target proteins per compound (1).…”

“…However, off-target activity can lead to adverse drug reactions (ADR) such as the case with fenfluramine and torcetrapib, 2 agents halted in development because of fatal hypertension that was the consequence of secondary target inhibition (1)(2)(3). Highlighting the promiscuity of small molecule inhibitors, a recent in silico screening of 213 Roche compounds revealed an average of 6.3 target proteins per compound (1). The standard approach for detecting off-target activity consists of screening compounds against panels of targets, often involving recombinant proteins in cell-free systems, and in silico prediction tools (1,4).…”

On the Relationship between Molecular Hit Rates in High-Throughput Screening and Molecular Descriptors

“…Other molecular properties such as ionization state, basicity, and presence of certain functional groups have also been found to influence promiscuity. [6][7][8][9][10] Hopkins et al 6 reported that compound promiscuity decreases with higher molecular weight (MW) based on HTS data. Diller and Hobbs 11 published a statistical analysis of a company's historical HTS data, in which they examined the relationship between physicochemical properties, substructures, and likelihood of displaying biological activity, irrespective of target class.…”