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<p>Achieving selectivity among ATP-competitive kinase inhibitors remains a major challenge due to the high conservation of the ATP-binding pocket across the kinome. Although most kinase inhibitors target the ATP-binding site, ATP-mimicking compounds remain relatively uncommon due to concerns regarding selectivity. Here, we report the structural and biophysical characterization of the atypical serine/threonine kinase haploid germ cell-specific nuclear protein kinase (HASPIN) with two ATP-mimicking inhibitors, LJ-5157 and LJ-5242. Crystal structures of HASPIN in complex with LJ-5157 and with LJ-5242 were determined at resolutions of 1.74 Å and 1.88 Å, respectively, revealing ATP-like binding modes within the catalytic pocket. Structural analysis showed that the regulatory and catalytic spines of HASPIN are preorganized through extensive hydrophobic packing, particularly within the N-lobe, stabilizing the αC helix independently of nucleotide binding. Despite similar binding modes, microscale thermophoresis measurements demonstrated that LJ-5242 binds ~&#xa0;10-fold more tightly than LJ-5157. LJ-5157 and LJ-5242 exhibited selective HASPIN inhibition, with LJ-5242 showing ~ 10-fold and ~ 100-fold higher potency and selectivity in kinase inhibition and antiproliferative activity assays, respectively. These findings demonstrate that the distinctive architecture of the HASPIN ATP-binding pocket enables selective recognition of ATP-mimicking inhibitors and provides a framework for designing kinase inhibitors that retain ATP-like scaffolds while achieving selectivity.</p>

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Structural insights into selective recognition of ATP-mimicking inhibitors by the atypical kinase HASPIN

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月14日

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  • Sang Won Cheon,
  • Yun A. Yum,
  • Donghwan Ku,
  • Sung Chul Jang,
  • Vikas R. Aswar,
  • Dnyandev B. Jarhad,
  • Yoonyoung Heo,
  • Hyoun Sook Kim,
  • Sang Kook Lee,
  • Lak-Shin Jeong,
  • Byung Woo Han

摘要

Achieving selectivity among ATP-competitive kinase inhibitors remains a major challenge due to the high conservation of the ATP-binding pocket across the kinome. Although most kinase inhibitors target the ATP-binding site, ATP-mimicking compounds remain relatively uncommon due to concerns regarding selectivity. Here, we report the structural and biophysical characterization of the atypical serine/threonine kinase haploid germ cell-specific nuclear protein kinase (HASPIN) with two ATP-mimicking inhibitors, LJ-5157 and LJ-5242. Crystal structures of HASPIN in complex with LJ-5157 and with LJ-5242 were determined at resolutions of 1.74 Å and 1.88 Å, respectively, revealing ATP-like binding modes within the catalytic pocket. Structural analysis showed that the regulatory and catalytic spines of HASPIN are preorganized through extensive hydrophobic packing, particularly within the N-lobe, stabilizing the αC helix independently of nucleotide binding. Despite similar binding modes, microscale thermophoresis measurements demonstrated that LJ-5242 binds ~ 10-fold more tightly than LJ-5157. LJ-5157 and LJ-5242 exhibited selective HASPIN inhibition, with LJ-5242 showing ~ 10-fold and ~ 100-fold higher potency and selectivity in kinase inhibition and antiproliferative activity assays, respectively. These findings demonstrate that the distinctive architecture of the HASPIN ATP-binding pocket enables selective recognition of ATP-mimicking inhibitors and provides a framework for designing kinase inhibitors that retain ATP-like scaffolds while achieving selectivity.