2021年11月18日 · Activating mutations in MYD88 promote malignant cell growth and survival through hematopoietic cell kinase (HCK)-mediated activation of Bruton tyrosine kinase (BTK). Ibrutinib binds to BTKCys481 and is active in B-cell malignancies driven by mutated MYD88.

2022年5月31日 · Data showing that BTK C481F and BTK C481Y interact with and activate HCK suggest that these kinase-deficient BTK mutants might disrupt the autoinhibitory conformation of HCK, enabling HCK to autophosphorylate and activate itself (39).

2024年3月7日 · Here, we show that KIN-8194, a dual inhibitor of BTK and HCK with in vivo activity against Myd88-L265P-driven diffuse large B-cell lymphoma and Waldenström Macroglobulinemia, has a potent...

2019年11月13日 · We therefore describe a novel, highly potent non-covalent dual HCK and BTK inhibitor that is well tolerated in mice, shows selective killing of MYD88 mutated WM and ABC DLBCL cells, and can overcome mutated BTK Cys481 related ibrutinib resistance.

KINOMEscan® 和活细胞靶标参与研究（KiNativ™ 分析和活细胞 ATP-生物素竞争测定）均证实了 HCK 和 BTK 双重抑制。 在这些研究中，KIN-8194 显示出对 HCK (IC50<0.495nM) 和 BTK (IC50=0.915nM) 的强烈抑制，并在野生型和突变的 BTKCys481 WM 和 ABC DLBC

2021年11月11日 · KIN-8194 is a highly potent dual HCK and BTK inhibitor with superior antitumor activity over ibrutinib in MYD88-mutated B-cell lymphomas. KIN-8194 overcomes ibrutinib resistance with a survival benefit in TMD-8 ABC DLBCL xenografted mice …

2024年11月5日 · Both PROTACs showed robust bioavailability and degradation of HCK and BTK in murine TMD8 xenograft models as well as potent tumor suppression. These studies provide a framework for advancing bifunctional HCK/BTK PROTACs for treating MYD88-mutated lymphomas, including covalent BTK-inhibitor resistant disease carrying BTKCys481 mutations.

2022年5月31日 · The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib irreversibly binds BTK at Cys⁴⁸¹, inhibiting its kinase activity and thus blocking transduction of B cell receptor (BCR) signaling. Although ibrutinib is durably effective in patients with B cell malignancies, many patients still deve …

2024年11月5日 · These studies provide a framework for advancing bifunctional HCK/BTK PROTACs for treating MYD88-mutated lymphomas, including covalent BTK-inhibitor resistant disease carrying BTKCys481 mutations.

The BTK L528W mutant can activate HCK. (a-f) Kinase activity of HCK in the presence or absence of full-length BTK L528W mutant was compared in a western blot assay by monitoring PLCγ1 phosphorylation (pY783 antibody) and HCK autophosphorylation (pY antibody).