Journal: bioRxiv

Article Title: Discovery of novel brain permeable human ACSS2 inhibitors for blocking breast cancer brain metastatic growth

doi: 10.1101/2023.12.22.573073

Figure Lengend Snippet: (A) Oral CNS Scoring profile score vs. logS of AD-2441 and its analogs, including two currently known control inhibitors, VY-3-249 and VY-3-135. Plot showing the StarDrop V7 (Optibrium, Ltd., Cambridge, UK)–derived logS versus a multimetric oral CNS profile score. Score composition and importance of each contributor: logS = 0.8, logP = 0.6, logD = 0.6, BBB category = 0.55, BBB log(brain:blood) = 0.55, P-gp category = 0.5, HIA = 0.4, hERG pIC50 = 0.2, 2D6 affinity category = 0.16, 2C9 pKi = 0.16, PPB90 category = 0.1. The size of the circle correlates with the corresponding score or probability. (B) Computational and SPR-based validation pipeline for the discovery of novel ACSS2 inhibitors.

Article Snippet: We utilized a computational analysis, applying the P450 module in StarDrop V7 software (Optibrium, Ltd., Cambridge, UK) to predict each compound’s primary metabolizing Cytochrome P450 isoforms using the WhichP450™ model [ , , ].

Techniques: Derivative Assay

Journal: bioRxiv

Article Title: Discovery of novel brain permeable human ACSS2 inhibitors for blocking breast cancer brain metastatic growth

doi: 10.1101/2023.12.22.573073

Figure Lengend Snippet: (A) Prediction of the major metabolizing CYP isoforms for AD-2441 and analogs. The majority of compounds are predicted to be metabolized by the 3A4 isoform, except AD-1363, which is predicted to be metabolized by the 2D6 isoform. ( B ) A lower boundary for predicted 3A4 affinity of AD-2441 and analogs using the hydrogen bond and dehydration scoring function (HYDE) implemented in SeeSAR12.1. 2D6 affinity category of AD-2441 and analogs as predicted by the Stardrop P450 module. ( C ) Overall composite site lability (CSL) score and number of labile sites (for metabolism) for AD-2441 and analogs. A lower CSL score indicates a more stable molecule. The prediction was achieved using the StarDrop (version 7) P450 module. (D) SPR-derived Response Units (RU) at 25 μM injection of VY-3-249, AD-5584, and AD-8007 to immobilized human ACSS2 or human ACSS1. Experiments were performed in triplicate (n=3), and statistical significance was performed using paired comparison and means compared using the Tukey method. Boxblots display the mean (line in the box and value to the right), box size represents SEM, and whiskers the confidence interval at α of 90%.

Article Snippet: We utilized a computational analysis, applying the P450 module in StarDrop V7 software (Optibrium, Ltd., Cambridge, UK) to predict each compound’s primary metabolizing Cytochrome P450 isoforms using the WhichP450™ model [ , , ].

Techniques: Derivative Assay, Injection, Comparison