Dataset Information

Physicochemistry of Cereblon Modulating Drugs Determines Pharmacokinetics and Disposition.

ABSTRACT: Immunomodulatory drugs (IMiDs) thalidomide, lenalidomide, and pomalidomide engage cereblon and mediate a protein interface with neosubstrates such as zinc finger transcription factors promoting their polyubiquitination and degradation. The IMiDs have garnered considerable excitement in drug discovery, leading to exploration of targeted protein degradation strategies. Although the molecular modes-of-action of the IMiDs and related degraders have been the subject of intense research, their pharmacokinetics and disposition have been relatively understudied. Here, we assess the effects of physicochemistry of the IMiDs, the phthalimide EM-12, and the candidate drug CC-220 (iberdomide) on lipophilicity, solubility, metabolism, permeability, intracellular bioavailability, and cell-based potency. The insights yielded in this study will enable the rational property-based design and development of targeted protein degraders in the future.

SUBMITTER: Kong NR

PROVIDER: S-EPMC8591734 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Physicochemistry of Cereblon Modulating Drugs Determines Pharmacokinetics and Disposition.

Kong Nikki R NR Liu Hu H Che Jianwei J Jones Lyn H LH

ACS medicinal chemistry letters 20211008 11

Immunomodulatory drugs (IMiDs) thalidomide, lenalidomide, and pomalidomide engage cereblon and mediate a protein interface with neosubstrates such as zinc finger transcription factors promoting their polyubiquitination and degradation. The IMiDs have garnered considerable excitement in drug discovery, leading to exploration of targeted protein degradation strategies. Although the molecular modes-of-action of the IMiDs and related degraders have been the subject of intense research, their pharmac ...[more]

PMID: 34795877

Similar Datasets

Project description:The objective of this study was to systematically assess literature datasets and quantitatively analyze metformin PK in plasma and some tissues of nine species. The pharmacokinetic (PK) parameters and profiles of metformin in nine species were collected from the literature. Based on a simple allometric scaling, the systemic clearances (CL) of metformin in these species highly correlate with body weight (BW) (R2 = 0.85) and are comparable to renal plasma flow in most species except for rabbit and cat. Reported volumes of distribution (VSS) varied appreciably (0.32 to 10.1 L/kg) among species. Using the physiological and anatomical variables for each species, a minimal physiologically based pharmacokinetic (mPBPK) model consisting of blood and two tissue compartments (Tissues 1 and 2) was used for modeling metformin PK in the nine species. Permeability-limited distribution (low fd1 and fd2) and a single tissue-to-plasma partition coefficient (Kp) value for Tissues 1 and 2 were applied in the joint mPBPK fitting. Nonlinear regression analysis for common tissue distribution parameters along with species-specific CL values reasonably captured the plasma PK profiles of metformin across most species, except for rat and horse with later time deviations. In separate fittings of the mPBPK model to each species, Tissue 2 was considered as slowly-equilibrating compartment consisting of muscle and skin based on in silico calculations of the mean transit times through tissues. The well-fitted mPBPK model parameters for absorption and disposition PK of metformin for each species were compared with in vitro/in vivo results found in the literature with regard to the physiological details and physicochemical properties of metformin. Bioavailability and absorption rates decreased with the increased BW among the species. Tissues such as muscle dominate metformin distribution with low permeability and partitioning while actual tissue concentrations found in rats and mice show likely transporter-mediated uptake in liver, kidney, and gastrointestinal tissues. Metformin has diverse pharmacologic actions, and this assessment revealed allometric relationships in its absorption and renal clearance but considerable variability in actual and modeled tissue distribution probably caused by transporter differences.

Dataset Information

Physicochemistry of Cereblon Modulating Drugs Determines Pharmacokinetics and Disposition.

Publications

Physicochemistry of Cereblon Modulating Drugs Determines Pharmacokinetics and Disposition.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets