Orthogonal IMiD-Degron Pairs Induce Selective Protein Degradation in Cells.

Immunomodulatory imide drugs (IMiDs) including thalidomide, lenalidomide, and pomalidomide, can be used to induce degradation of a protein of interest that is fused to a short zinc finger (ZF) degron motif. These IMiDs, however, also induce degradation of endogenous neosubstrates, including IKZF1 and IKZF3. To improve degradation selectivity, we took a bump-and-hole approach to design and screen bumped IMiD analogs against 8380 ZF mutants. This yielded a bumped IMiD analog that induces efficient degradation of a mutant ZF degron, while not affecting other cellular proteins, including IKZF1 and IKZF3. In proof-of-concept studies, this system was applied to induce efficient degradation of TRIM28, a disease-relevant protein with no known small molecule binders. We anticipate that this system will make a valuable addition to the current arsenal of degron systems for use in target validation.

In Vivo Half-Life Extension of BMP1/TLL Metalloproteinase Inhibitors Using Small-Molecule Human Serum Albumin Binders.

Reducing the required frequence of drug dosing can improve the adherence of patients to chronic treatments. Hence, drugs with longer in vivo half-lives are highly desirable. One of the most promising approaches to extend the in vivo half-life of drugs is conjugation to human serum albumin (HSA). In this work, we describe the use of AlbuBinder 1, a small-molecule noncovalent HSA binder, to extend the in vivo half-life and pharmacology of small-molecule BMP1/TLL inhibitors in humanized mice (HSA KI/KI). A series of conjugates of AlbuBinder 1 with BMP1/TLL inhibitors were prepared. In particular, conjugate c showed good solubility and a half-life extension of >20-fold versus the parent molecule in the HSA KI/KI mice, reaching half-lives of >48 h with maintained maximal inhibition of plasma BMP1/TLL. The same conjugate showed a half-life of only 3 h in the wild-type mice, suggesting that the half-life extension was principally due to specific interactions with HSA. It is envisioned that conjugation to AlbuBinder 1 should be applicable to a wide range of small molecule or peptide drugs with short half-lives. In this context, AlbuBinders represent a viable alternative to existing half-life extension technologies.

Revisiting the application of Immobilized Artificial Membrane (IAM) chromatography to estimate in vivo distribution properties of drug discovery compounds based on the model of marketed drugs.

Immobilized Artificial Membrane (IAM) chromatography columns have been used to model the in vivo distribution of drug discovery compounds. Regis Technologies Inc., the manufacturer, had to replace the silica support and consequently introduced a new IAM.PC.DD2 column that shows slightly different selectivity towards acidic and basic compounds. The application of the new IAM.PC.DD2 columns has been evaluated and the in vivo distribution models have been compared with the previous batches of columns. It was found that due to the improved endcapping of the silica, some of the positively charged drug molecules showed shorter retention than previously published. Therefore, the column system suitability data have been updated. However, these differences do not significantly affect the previously published models for the volume of distribution, brain tissue binding and drug efficiency. Therefore, the published models can be used with the new IAM.PC.DD2 columns.

Using Physicochemical Measurements to Influence Better Compound Design.

During the past decade, the physicochemical quality of molecules under investigation at all stages of the drug discovery process has come under particular scrutiny. The issues associated with excessive lipophilicity and poor solubility in particular are many and varied, ranging from poor outcomes in screening campaigns to promiscuity, limited and/or poorly predictable pharmacokinetic exposure, and, ultimately, greater chances of clinical failure. In this review, contemporary methods to secure key measurements are described along with their relevance to understanding the behavior of molecules in environments pertinent to pharmacological activity. Together, the various measurements contribute to predictive models of both the physicochemical properties themselves and the outcomes they influence.