In vitro activity of novel KIT/PDGFRA switch pocket kinase inhibitors against mutations associated with drug-resistant GI stromal tumors.
2010; Lippincott Williams & Wilkins; Volume: 28; Issue: 15_suppl Linguagem: Inglês
10.1200/jco.2010.28.15_suppl.10007
ISSN1527-7755
AutoresMichael C. Heinrich, Scott Wise, Molly M. Hood, Bryan D. Smith, Michael D. Kaufman, Weiguang Lu, Yigui Wang, Diana Griffith, Darren Flynn, Jonathan A. Fletcher,
Tópico(s)Platelet Disorders and Treatments
Resumo10007 Background: Most gastrointestinal stromal tumors (GISTs) harbor mutant KIT or PDGFRA kinases, which are targets of imatinib (IM) or sunitinib (SU). Resistance to IM or SU is commonly due to the acquisition of secondary mutations that markedly reduce the potency of kinase inhibitors. Both IM and SU bind to the KIT/PDGFRA ATP binding pocket. KIT and PDGFRA kinases possess negative and positive regulatory domains that modulate kinase activity by competitive binding into the switch pocket domain. Switch pocket kinase inhibitors (SPKIs) occupy this pocket and block enzymatic activity. We developed SPKIs with low nanomolar potency against wild-type KIT/PDGFRA kinases. Methods: We tested the activity of three SPKIs (DP-2976, DP-3636, DP-4444) in enzymatic assays using various wild-type and recombinant KIT kinases. In addition, a panel of kinase mutants was biochemically profiled for sensitivity to these SPKIs using several cell line models, including GIST cell lines derived from imatinib-resistant tumor clones. Results: All three SPKIs were very potent (5-10 nM IC50) against wild-type KIT and PDGFRA. In addition, these compounds maintained their potency against representative GIST-associated drug resistance mutations (V654A, T670I, D816H, D816V). DP-2976 and DP-3636 were also potent against the pan drug-resistant PDGFRA D842V mutation with IC50s of 50 and 20 nM, respectively. To confirm these observations in a GIST cellular context, we tested the relative potency of these compounds against two previously described IM-resistant GIST cell lines (exon 11 + V654A, exon 11 + D820A). All three compounds were significantly more potent than IM or SU for both cell lines. These results also correlated with enhanced inhibition of downstream signaling pathways, cellular proliferation and survival. Conclusions: DP-2976, DP-3636, and DP-4444 have markedly superior in vitro potency compared with IM or SU against a panel of GIST-relevant mutant kinases. Based on these results, we hypothesize that these compounds might have useful clinical activity against drug- resistant GIST. Further preclinical studies are indicated to develop these compounds for human clinical studies. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Deciphera Deciphera, MolecularMD Novartis Novartis
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