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. 2024 Aug;38(8):1843-1847.
doi: 10.1038/s41375-024-02282-y. Epub 2024 May 15.

Repurposing pexmetinib as an inhibitor of TKI-resistant BCR::ABL1

Diletta Fontana  1 , Federica Malighetti  1 , Matteo Villa  1 , Alfonso Zambon  2 , Carlo Gambacorti-Passerini  1   3 , Luca Mologni  4
Affiliations

Repurposing pexmetinib as an inhibitor of TKI-resistant BCR::ABL1

Diletta Fontana et al. Leukemia. 2024 Aug.
No abstract available

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Identification of pexmetinib activity in Ba/F3T315I cells.
A Scheme of the screening strategy. The sensitivity of Ba/F3 and Ba/F3T315I cells to 10 µM inhibitors was assessed in 96-well plates. B IC50 ratio (parental/T315I) of 27 inhibitors that passed phase 1 (listed in Supplementary Fig. 1); the indicated three compounds were selected after phase 2 of the screening. C Ba/F3 cells, parental or expressing BCR::ABL1T315I mutant, were treated with increasing concentrations of the indicated inhibitors. Dose-response curves were obtained by non-linear fitting of normalized cell growth data. D A summary of the experimental therapeutic indexes (calculated as the [Ba/F3IL3]/[Ba/F3BCR::ABL1] IC50 ratio) is reported for WT and mutant cells (T315I, G250E, Y253F, E255K, E255V); pexmetinib and ponatinib pass the tenfold therapeutic index mark for all mutations, indicating they can safely be used against these mutants, without killing non-transformed cells. IM imatinib; NIL nilotinib; DAS dasatinib; BOS bosutinib; PON ponatinib; REB rebastinib; PEX pexmetinib. E Inhibition of recombinant WT and T315I ABL1 kinase by pexmetinib in an in vitro kinase assay.
Fig. 2
Fig. 2. Effects of pexmetinib on human CML cells.
A Proliferation of human Ph+ KCL22 cells carrying the T315I mutation treated with the indicated inhibitors. Dose-response curves (upper panels) and time-course experiments (lower panels) are shown. KCL22-DasR and KCL22-BosR indicate KCL22 cells selected for resistance to dasatinib and bosutinib, respectively. B Inhibition of BCR::ABL1T315I autophosphorylation in drug-resistant KCL22 cells, shown by western blot using phospho-specific (pABL1) and total ABL1 antibodies. C Summary of drug-resistant KCL22 cells growth inhibition data, shown as IC50 fold-change values relative to parental KCL22, highlighting the loss of potency in resistant cells; Ph− cells (SUPM2) are shown as a reference of unspecific toxicity. D Tumor growth of KCL-DasR xenografts in nude mice treated daily with vehicle (n = 6), dasatinib (20 mg/kg p.o.; n = 5), or pexmetinib (40 mg/kg i.p.; n = 5). *p < 0.05 versus vehicle and dasatinib. Mice were injected subcutaneously with 8 × 106 cells in right flank; treatments started when tumors were measurable (30 mm3). E Inhibition of colony formation of BCR::ABL1-negative, WT and T315I patient-derived bone marrow myeloid cells by pexmetinib (3–10 μM), dasatinib (3–10 nM) and imatinib (0.3–1 μM); 2 × 105 cells were seeded in methylcellulose and colonies were counted after 14 days. The data represent the normalized mean ± SD of triplicate experiments. The average of two T315I patients is reported. *p < 0.05; **p < 0.01; ***p < 0.001 versus vehicle. Statistical significance is calculated by unpaired, two-tailed Student’s t-test. F Molecular docking of pexmetinib (gray sticks) in T315I-mutated ABL1 kinase shown by ribbon representation. The DFG motif is in pink color. G Superposition of pexmetinib (gray) and axitinib (green) bound to ABL1T315I kinase. Docking studies were performed using the Maestro suite from Schrodinger. IM imatinib; NIL nilotinib; DAS dasatinib; BOS bosutinib; PON ponatinib; PEX pexmetinib.
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