SPLicing inhibitor sulfonAMides (SPLAMs)

New aryl sulfonamides designed to target DCAF family of E3 ligases

For a long time, Indisulam and a few other clinically tested aryl sulfonamides such as Tasisulam and chloroquinoxaline sulfonamide (CQS) remained compounds with pronounced selective in vitro anticancer activity with unclear mechanism of action.

Recent extensive investigations in cancer genome sequencing together with X-Ray crystallography and cryo-electron microscopy showed that these compounds (also known as SPLAMs - SPLicing inhibitor sulfonAMides) act as a “molecular glue” to induce degradation via binding to DCAF15. This insight provided structural and mechanistic data that significantly extend our understanding of their mode of action.

E7820

Indisulam

Tasisulam

CQS

Based on these emerging data we have designed several focused compound libraries of aryl sulfonamides both using selections from our Screening Collection and employing enumerations of new REAL compounds that we can confidently synthesize:

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Library design

Recent studies demonstrated that SPLAMs promote the interaction between RBM39 and DCAF15 E3 ligase receptor, leading to ubiquitination of RBM39 and proteasome-mediated degradation.

According to the structural data Indisulam and Tasisulam bind DCAF15 in an overall configuration similar to E7820, maintaining the backbone hydrogen bonds from the sulfonyl groups to DCAF15 Ala234 and Phe235 and the water mediated hydrogen bonds. However, the methyl to hydrogen substitution at C4 in Indisulam limits the hydrophobic interactions with DCAF15 Val477 and Val556, while Tasisulam lacks the indole NH hydrogen bond to the backbone carbonyl of DCAF15 Phe231.

Based on the available structural data we have designed DCAF15 Focused Library from our stock Screening Collection using the following approach:

  • Generation and selection of close chemotypes/scaffolds based on diverse aryl and heteroaryl (five-membered inclusive) sulfonamides;
  • Further selection based on pharmacophore modelling and docking results using available structural data of DCAF15;
  • MedChem filtering according to criteria of lead/drug likeness.
Docking results

Figure 1. Docking results

Figure 2. Examples of SPLAM analogues

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