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    1. karim2001khoury 19 Feb 2026
      FLT3 D835 Mutations Confer Differential Resistance to Type II FLT3 Inhibitors

      [Paper-level Aggregated] PMCID: PMC4675689

      Evidence Type(s): Oncogenic, Predictive, Functional

      Justification: Oncogenic: The D835 mutations are reported to cause FLT3 TKI resistance in patients, indicating their role in tumorigenesis and cancer progression. Predictive: The study suggests that specific D835 mutations can predict the level of resistance to type II FLT3 inhibitors, which can inform treatment decisions. Functional: The text discusses the functional implications of D835 mutations on the stability of the DFG-out conformation and their impact on inhibitor binding, demonstrating the functional consequences of these mutations.

      Gene→Variant (gene-first): FLT3(2322):D835 FLT3(2322):D835A/E FLT3(2322):D835H FLT3(2322):D835V/Y FLT3(2322):D835E/N FLT3(2322):D835N/E FLT3(2322):D835Y/V

      Genes: FLT3(2322)

      Variants: D835 D835A/E D835H D835V/Y D835E/N D835N/E D835Y/V

      CIViC paper-level aggregated PMC4675689
    2. karim2001khoury 19 Feb 2026
      Our data suggest that some clinically relevant D835 mutants retain sensitivity to type II inhibitors at clinically achievable drug concentrations and propose a molecular mechanism for differences in sensitivity for indiv

      [Paragraph-level] PMCID: PMC4675689 Section: RESULTS PassageIndex: 8

      Evidence Type(s): Predictive, Oncogenic

      Justification: Predictive: The passage discusses the sensitivity of D835 mutants to type II inhibitors, indicating a correlation with treatment response, which aligns with predictive evidence. Oncogenic: The mention of D835 mutations and their role in mediating resistance and sensitivity to FLT3 TKIs suggests that these somatic variants contribute to tumor development or progression.

      Gene→Variant (gene-first): 2322:D835 2322:D835N/E

      Genes: 2322

      Variants: D835 D835N/E

      CIViC paragraph-level PMC4675689 Predictive Oncogenic
    3. karim2001khoury 19 Feb 2026
      Unlike the mutations discussed above, the models of the moderately resistant D835H mutation based each of the two template structures differ from each other. We assume the model based on the quizartinib template is more

      [Paragraph-level] PMCID: PMC4675689 Section: RESULTS PassageIndex: 7

      Evidence Type(s): Predictive, Functional

      Justification: Predictive: The passage discusses the D835H mutation's resistance to type II inhibitors, indicating a correlation with treatment response and sensitivity to specific therapies. Functional: The passage describes how the D835H mutation alters the binding mode and hydrogen bond formation, indicating a change in molecular function related to inhibitor interaction.

      Gene→Variant (gene-first): 2322:D835H

      Genes: 2322

      Variants: D835H

      CIViC paragraph-level PMC4675689 Predictive Functional
    4. karim2001khoury 19 Feb 2026
      The most highly resistant mutants (D835Y/V/I/F) are large and bulky hydrophobic amino acid residues. In addition to an inability to hydrogen bond with S838, these large side chains are predicted to be sterically incompat

      [Paragraph-level] PMCID: PMC4675689 Section: RESULTS PassageIndex: 6

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how the D835Y/V variant alters molecular interactions and structural compatibility, indicating a change in biochemical function related to steric hindrance and hydrogen bonding. Oncogenic: The mention of "highly resistant mutants" suggests that the D835Y/V variant contributes to tumor development or progression by conferring resistance, which is characteristic of oncogenic behavior.

      Gene→Variant (gene-first): 2322:D835Y/V

      Genes: 2322

      Variants: D835Y/V

      CIViC paragraph-level PMC4675689 Functional Oncogenic
    5. karim2001khoury 19 Feb 2026
      The most sensitive mutants (D835E/N) are characterized by the predicted preservation of the hydrogen bond between D835 and S838 based on models utilizing both the apo and holo structures as templates. Side chains of the

      [Paragraph-level] PMCID: PMC4675689 Section: RESULTS PassageIndex: 5

      Evidence Type(s): Functional, Predictive

      Justification: Functional: The passage discusses how the D835E/N mutations alter molecular interactions, specifically the formation of hydrogen bonds and the conservation of the alpha-helix structure, which affects inhibitor binding. Predictive: The passage indicates that the D835E/N variants are associated with sensitivity to type II inhibitors, suggesting a correlation with treatment response.

      Gene→Variant (gene-first): 2322:D835 2322:D835E/N

      Genes: 2322

      Variants: D835 D835E/N

      CIViC paragraph-level PMC4675689 Functional Predictive
    6. karim2001khoury 19 Feb 2026
      It is not straightforward to rationalize the effect of mutations near or in the short alpha-helix on the distant drug-binding active site. Nevertheless, it has been suggested that the short alpha-helix, which is part of

      [Paragraph-level] PMCID: PMC4675689 Section: RESULTS PassageIndex: 4

      Evidence Type(s): Predictive, Functional

      Justification: Predictive: The passage discusses the correlation of D835 mutations with resistance to type II inhibitors, indicating a relationship between the variant and treatment response. Functional: The passage describes the impact of D835 mutations on the short alpha-helix and its potential effect on the drug-binding site, suggesting an alteration in molecular function related to drug interaction.

      Gene→Variant (gene-first): 2322:D835

      Genes: 2322

      Variants: D835

      CIViC paragraph-level PMC4675689 Predictive Functional
    7. karim2001khoury 19 Feb 2026
      Type II inhibitors bind to the conformation coupled to the DFG-out position of the kinase AL (residues 829-856 in FLT3). As previously noted, D835 is predicted to play a critical role in the stabilization of the DFG-out

      [Paragraph-level] PMCID: PMC4675689 Section: RESULTS PassageIndex: 3

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses how the D835 variant alters the molecular function of the kinase by stabilizing the DFG-out conformation and forming interactions that affect the structure of the alpha-helix.

      Gene→Variant (gene-first): 2322:D835

      Genes: 2322

      Variants: D835

      CIViC paragraph-level PMC4675689 Functional
    8. karim2001khoury 19 Feb 2026
      We profiled all D835 substitutions previously reported to cause FLT3 TKI resistance in patients, as well as D835 mutations occurring in patients as cataloged in the Sanger COSMIC database or the Cancer Genome Atlas. Inhi

      [Paragraph-level] PMCID: PMC4675689 Section: RESULTS PassageIndex: 2

      Evidence Type(s): Predictive, Oncogenic

      Justification: Predictive: The passage discusses how various D835 substitutions correlate with resistance to FLT3 inhibitors, indicating their predictive value regarding treatment response. Oncogenic: The D835 mutations are reported to cause resistance in patients, suggesting that these somatic variants contribute to tumor development or progression.

      Gene→Variant (gene-first): 2322:D835 2322:D835A/E 2322:D835H 2322:D835V/Y

      Genes: 2322

      Variants: D835 D835A/E D835H D835V/Y

      CIViC paragraph-level PMC4675689 Predictive Oncogenic
    9. karim2001khoury 19 Feb 2026
      Our data suggest that some clinically relevant D835 mutants retain sensitivity to type II inhibitors at clinically achievable drug concentrations and propose a molecular mechanism for differences in sensitivity for indiv

      [Paragraph-level] PMCID: PMC4675689 Section: RESULTS PassageIndex: 8

      Evidence Type(s): Predictive, Oncogenic

      Justification: Predictive: The passage discusses the sensitivity of D835 mutants to type II inhibitors, indicating a correlation with treatment response, which aligns with predictive evidence. Oncogenic: The mention of D835 mutations and their role in mediating resistance and sensitivity to FLT3 TKIs suggests that these somatic variants contribute to tumor development or progression.

      Gene→Variant (gene-first): 2322:D835 2322:D835N/E

      Genes: 2322

      Variants: D835 D835N/E

      CIViC paragraph-level PMC4675689 Predictive Oncogenic
    10. karim2001khoury 19 Feb 2026
      Unlike the mutations discussed above, the models of the moderately resistant D835H mutation based each of the two template structures differ from each other. We assume the model based on the quizartinib template is more

      [Paragraph-level] PMCID: PMC4675689 Section: RESULTS PassageIndex: 7

      Evidence Type(s): Predictive, Functional

      Justification: Predictive: The passage discusses the D835H mutation's resistance to type II inhibitors, indicating a correlation with treatment response and sensitivity to specific therapies. Functional: The passage describes how the D835H mutation alters the binding mode and hydrogen bond formation, indicating a change in molecular function related to inhibitor interaction.

      Gene→Variant (gene-first): 2322:D835H

      Genes: 2322

      Variants: D835H

      CIViC paragraph-level PMC4675689 Predictive Functional
    11. karim2001khoury 19 Feb 2026
      The most highly resistant mutants (D835Y/V/I/F) are large and bulky hydrophobic amino acid residues. In addition to an inability to hydrogen bond with S838, these large side chains are predicted to be sterically incompat

      [Paragraph-level] PMCID: PMC4675689 Section: RESULTS PassageIndex: 6

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses how the D835Y/V variant alters molecular interactions and structural compatibility, indicating a change in biochemical function related to steric hindrance and hydrogen bonding. Oncogenic: The mention of "highly resistant mutants" suggests that the D835Y/V variant contributes to tumor development or progression by conferring resistance, which is characteristic of oncogenic behavior.

      Gene→Variant (gene-first): 2322:D835Y/V

      Genes: 2322

      Variants: D835Y/V

      CIViC paragraph-level PMC4675689 Functional Oncogenic
    12. karim2001khoury 19 Feb 2026
      The most sensitive mutants (D835E/N) are characterized by the predicted preservation of the hydrogen bond between D835 and S838 based on models utilizing both the apo and holo structures as templates. Side chains of the

      [Paragraph-level] PMCID: PMC4675689 Section: RESULTS PassageIndex: 5

      Evidence Type(s): Functional, Predictive

      Justification: Functional: The passage discusses how the D835E/N mutations alter molecular interactions, specifically the formation of hydrogen bonds and the conservation of the alpha-helix structure, which affects inhibitor binding. Predictive: The passage indicates that the D835E/N variants are associated with sensitivity to type II inhibitors, suggesting a correlation with treatment response.

      Gene→Variant (gene-first): 2322:D835 2322:D835E/N

      Genes: 2322

      Variants: D835 D835E/N

      CIViC paragraph-level PMC4675689 Functional Predictive
    13. karim2001khoury 19 Feb 2026
      It is not straightforward to rationalize the effect of mutations near or in the short alpha-helix on the distant drug-binding active site. Nevertheless, it has been suggested that the short alpha-helix, which is part of

      [Paragraph-level] PMCID: PMC4675689 Section: RESULTS PassageIndex: 4

      Evidence Type(s): Predictive, Functional

      Justification: Predictive: The passage discusses the correlation of D835 mutations with resistance to type II inhibitors, indicating a relationship between the variant and treatment response. Functional: The passage describes the impact of D835 mutations on the short alpha-helix and its potential effect on the drug-binding site, suggesting an alteration in molecular function related to drug interaction.

      Gene→Variant (gene-first): 2322:D835

      Genes: 2322

      Variants: D835

      CIViC paragraph-level PMC4675689 Predictive Functional
    14. karim2001khoury 19 Feb 2026
      Type II inhibitors bind to the conformation coupled to the DFG-out position of the kinase AL (residues 829-856 in FLT3). As previously noted, D835 is predicted to play a critical role in the stabilization of the DFG-out

      [Paragraph-level] PMCID: PMC4675689 Section: RESULTS PassageIndex: 3

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses how the D835 variant alters the molecular function of the kinase by stabilizing the DFG-out conformation and forming interactions that affect the structure of the alpha-helix.

      Gene→Variant (gene-first): 2322:D835

      Genes: 2322

      Variants: D835

      CIViC paragraph-level PMC4675689 Functional
    15. karim2001khoury 19 Feb 2026
      We profiled all D835 substitutions previously reported to cause FLT3 TKI resistance in patients, as well as D835 mutations occurring in patients as cataloged in the Sanger COSMIC database or the Cancer Genome Atlas. Inhi

      [Paragraph-level] PMCID: PMC4675689 Section: RESULTS PassageIndex: 2

      Evidence Type(s): Predictive, Oncogenic

      Justification: Predictive: The passage discusses how various D835 substitutions correlate with resistance to FLT3 inhibitors, indicating their predictive value regarding treatment response. Oncogenic: The D835 mutations are reported to cause resistance in patients, suggesting that these somatic variants contribute to tumor development or progression.

      Gene→Variant (gene-first): 2322:D835 2322:D835A/E 2322:D835H 2322:D835V/Y

      Genes: 2322

      Variants: D835 D835A/E D835H D835V/Y

      CIViC paragraph-level PMC4675689 Predictive Oncogenic
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    pmc.ncbi.nlm.nih.gov/articles/PMC4675689/pdf/nihms697045.pdf