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. 2022 Jan 25;8:5. doi: 10.1038/s41421-021-00368-w

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© The Author(s) 2022

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 1 — a Chemical structures of TH-Z801 and TH-Z816 with exposed piperazines, structure of TH-Z814 with non-amine moiety. b Inhibitory activities of TH-Z816 on KRAS(G12D) measured by SOS-catalyzed nucleotide exchange assay with GDP as the incoming nucleotide. c ITC assay of the TH-Z816 (800 μM) and GDP-bound KRAS(G12D) (26 μM). d Crystal structure (PDB ID: 7EW9) of KRAS(G12D) bound to TH-Z816 (white stick). The binding pocket is formed by the α2-helix (green), switch-II (red), α3-helix (orange), P-loop (teal), and the central β-sheet (blue) of KRAS(G12D). e Fo-Fc maps of TH-Z816 (blue mesh, 2.5 σ; gray mesh, 1.5 σ) and Asp12 (pink mesh, 2.5 σ; gray mesh, 1.5 σ). f Interactions between TH-Z816 (green) and surrounding residues (orange). The hydrophobic sub-pocket is shown as a surface diagram. g The ionic bond (upper panel) and hydrogen bond (lower panel) between piperazine and Asp12.