Fig. 1: The structure and synthesis of VWK147, and its predicted binding mode at the CTD dimerization interface of an hHSP90 monomer. | Cell Death & Disease

Fig. 1: The structure and synthesis of VWK147, and its predicted binding mode at the CTD dimerization interface of an hHSP90 monomer.

From: Small-molecule inhibitor of C‑terminal HSP90 dimerization modulates autophagy and functions synergistically with mTOR inhibition to kill cisplatin-resistant cancer cells

Fig. 1: The structure and synthesis of VWK147, and its predicted binding mode at the CTD dimerization interface of an hHSP90 monomer.

A Synthesis of tripyrimidonamide 2 (VWK147) from benzoyl-protected tripyrimidonamide 1 (LSK82): (a) NaOH, MeOH, 80 °C, 5 h, 40% yield. B 2 (VWK147) (green) is predicted to bind to the dimerization interface parallel to helix H5 of the hHSP90 protomer (light blue). The side chains of 2 (VWK147) are in the same order as those it mimics in helix H5’ of the other protomer, although the binding mode is slightly shifted towards the N-terminus of H5. There, it forms a hydrogen bond to S677 with its carbonyl group. C Upon projection of the binding mode onto the hHSP90 CTD dimer from PDB ID 3Q6M, it becomes evident that the binding mode of 2 (VWK147) effectively precludes H5’ and, notably, H4’ of the opposing protomer (depicted in gray) from engaging with the dimerization interface constituted by H4 and H5 of the initial protomer.

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