2 TKIs for CML

30-40% will receive a next TKI after initial therapy

2.1 ATP Competitive Inhibitors

2.1.1 Dasatinib

2.1.2 Nilotinib

2.1.3 Bosutinib

2.1.4 Ponatinib

2.1.5 Olverembatinib (HQP1351)

2.1.6 Vodobatinib

2.1.7 ELVN-001

2.2 Allosteric Inhibitors

2.2.1 Asciminib

2.2.2 TGRX-678

2.2.3 TERN-701

Code

library(tidyverse)
library(gt)

Clinical Context

Approximately 30–40% of CML patients will require a next-line TKI after initial therapy. Understanding mechanistic differences across ATP-competitive and allosteric inhibitors is critical for rational treatment sequencing.

Code

tki_data <- tibble::tribble(
  ~Class, ~Agent, ~Generation, ~Binding_Site, ~Conformation, ~T315I, ~Selectivity, ~Key_Features, ~Status,
  
  # ATP-Competitive
  "ATP-Competitive", "Dasatinib", "2G", "ATP active site", "Active & inactive (DFG-in/out); type I/II", "No", "Broad (SRC, PDGFR, c-KIT, ephrin)", "Potent SRC inhibition; CNS penetration; pleural effusion risk", "Approved (1L, 2L+)",
  
  "ATP-Competitive", "Nilotinib", "2G", "ATP active site", "Inactive (DFG-out); type II", "No", "Moderate (PDGFR, c-KIT, DDR1)", "Optimized imatinib analogue; cardiovascular risk (PAOD); lipid/glucose effects", "Approved (1L, 2L+)",
  
  "ATP-Competitive", "Bosutinib", "2G", "ATP active site", "Active (DFG-in); type I", "No", "Moderate (SRC, TEC)", "Dual SRC/ABL inhibitor; GI toxicity prominent; less CV toxicity", "Approved (1L, 2L+)",
  
  "ATP-Competitive", "Ponatinib", "3G", "ATP active site", "Inactive (DFG-out); type II", "Yes", "Broad (FGFR, VEGFR, PDGFR, SRC, FLT3)", "Ethynyl linker spans T315I gatekeeper; AOEs; dose–response for efficacy & safety", "Approved (2L+/T315I)",
  
  "ATP-Competitive", "Olverembatinib", "3G", "ATP active site", "Inactive (DFG-out); type II", "Yes", "Broad (PDGFR, c-KIT, FGFR)", "QOD dosing; covers T315I & compound mutations; thrombocytopenia; approved in China", "Approved (CN); Phase II/III (global)",
  
  "ATP-Competitive", "Vodobatinib", "3G", "ATP active site", "Inactive (DFG-out); type II", "Yes", "More selective than ponatinib (reduced FGFR/VEGFR)", "Designed for improved selectivity vs ponatinib; combination partner with asciminib", "Phase II (VELOCITY)",
  
  "ATP-Competitive", "ELVN-001", "3G", "ATP active site", "Inactive (DFG-out); type II", "Yes", "Highly selective for ABL1 (minimal FGFR/VEGFR)", "T315I coverage with reduced off-target kinase activity; potentially lower vascular risk", "Phase I/II",
  
  # Allosteric
  "Allosteric (STAMP)", "Asciminib", "—", "Myristoyl pocket", "Induces inactive closed conformation", "Yes (200 mg BID)", "Highly selective for BCR::ABL1", "First-in-class STAMP inhibitor; combinable with ATP-site TKIs; myristoyl pocket mutations (A337V, P465S, V468F, I502L) confer resistance", "Approved (3L+, T315I); Phase III 1L",
  
  "Allosteric (STAMP)", "TGRX-678", "—", "Myristoyl pocket", "Induces inactive closed conformation", "Yes", "Highly selective for BCR::ABL1", "Next-gen STAMP; reported activity against some asciminib-resistant mutations; QD dosing", "Phase I/II (China-led)",
  
  "Allosteric (STAMP)", "TERN-701", "—", "Myristoyl pocket", "Induces inactive closed conformation", "Yes", "Highly selective — 0/468 kinase interactions", "Next-gen STAMP; superior potency vs asciminib on M244V & F359 mutations; QD dosing; Cave at 320/500 mg exceeds IC90 for most variants; P-gp inhibitor; no clinically relevant CYP interactions", "Phase I (CARDINAL)"
)

tki_data |>
  select(-Class) |>
  gt(groupname_col = NULL) |>
  
  # --- Row grouping by class ---
  tab_row_group(
    label = md("**Allosteric (Myristoyl Pocket / STAMP) Inhibitors**"),
    rows = which(tki_data$Class == "Allosteric (STAMP)")
  ) |>
  tab_row_group(
    label = md("**ATP-Competitive (Active-Site) Inhibitors**"),
    rows = which(tki_data$Class == "ATP-Competitive")
  ) |>
  
  # --- Column labels ---
  cols_label(
    Agent = "Agent",
    Generation = "Gen.",
    Binding_Site = "Binding Site",
    Conformation = "Conformation Targeted",
    T315I = "T315I Activity",
    Selectivity = "Kinase Selectivity",
    Key_Features = "Key Differentiating Features",
    Status = "Development Status"
  ) |>
  
  # --- Column widths ---
  cols_width(
    Agent ~ px(120),
    Generation ~ px(50),
    Binding_Site ~ px(110),
    Conformation ~ px(150),
    T315I ~ px(90),
    Selectivity ~ px(160),
    Key_Features ~ px(250),
    Status ~ px(140)
  ) |>
  
  # --- Styling ---
  tab_style(
    style = cell_text(weight = "bold"),
    locations = cells_body(columns = Agent)
  ) |>
  
  # T315I color coding
  tab_style(
    style = cell_text(color = "#059669", weight = "bold"),
    locations = cells_body(
      columns = T315I,
      rows = str_detect(T315I, "^Yes")
    )
  ) |>
  tab_style(
    style = cell_text(color = "#dc2626", weight = "bold"),
    locations = cells_body(
      columns = T315I,
      rows = T315I == "No"
    )
  ) |>
  
  # Highlight TERN-701 row
  tab_style(
    style = cell_fill(color = "#f0f9ff"),
    locations = cells_body(rows = Agent == "TERN-701")
  ) |>
  
  # Generation badge styling
  tab_style(
    style = cell_text(size = px(11), color = "#6b7280"),
    locations = cells_body(columns = Generation)
  ) |>
  
  # --- Header ---
  tab_header(
    title = md("**Mechanism of Action Comparison: BCR::ABL1 TKIs**"),
    subtitle = md("ATP-competitive and allosteric inhibitors — approved and investigational agents")
  ) |>
  
  # --- Footnotes ---
  tab_footnote(
    footnote = "STAMP = Specifically Targeting the ABL Myristoyl Pocket; DFG = Asp-Phe-Gly motif.",
    locations = cells_column_labels(columns = Conformation)
  ) |>
  tab_footnote(
    footnote = "Asciminib T315I activity requires higher dose (200 mg BID vs 80 mg QD for non-T315I).",
    locations = cells_body(columns = T315I, rows = Agent == "Asciminib")
  ) |>
  tab_footnote(
    footnote = "TERN-701 selectivity: 468 kinase assays tested, 0 significant interactions mapped (Parsons et al., EHA 2025).",
    locations = cells_body(columns = Selectivity, rows = Agent == "TERN-701")
  ) |>
  tab_footnote(
    footnote = "DDI profile: P-gp inhibitor; not a clinically relevant inhibitor of CYP3A4, CYP2C8, CYP2C19, or OATP1B1/3 (Anderson et al., SOHO 2025, Poster CML-586).",
    locations = cells_body(columns = Key_Features, rows = Agent == "TERN-701")
  ) |>
  
  # --- Source note ---
  tab_source_note(
    source_note = md("**Sources:** Anderson et al., SOHO 2025 Poster CML-586; Parsons et al., EHA 2025 (s425); product prescribing information; ClinicalTrials.gov.")
  ) |>
  tab_source_note(
    source_note = md("**Abbreviations:** 1L = first-line; 2G/3G = second/third generation; AOE = arterial occlusive event; BID = twice daily; Cave = average concentration; CN = China; CV = cardiovascular; GI = gastrointestinal; QD = once daily; QOD = every other day; VEGFR = vascular endothelial growth factor receptor.")
  ) |>
  
  # --- Global options ---
  tab_options(
    table.font.size = px(13),
    heading.title.font.size = px(18),
    heading.subtitle.font.size = px(13),
    row_group.font.weight = "bold",
    row_group.background.color = "#f1f5f9",
    column_labels.font.weight = "bold",
    column_labels.background.color = "#1e293b",
    table.border.top.color = "#1e293b",
    table.border.bottom.color = "#1e293b",
    footnotes.font.size = px(11),
    source_notes.font.size = px(11)
  ) |>
  tab_style(
    style = cell_text(color = "white"),
    locations = cells_column_labels()
  )

Table 2.1: Mechanism of Action Comparison of ATP-Competitive and Allosteric BCR::ABL1 Inhibitors

Agent	Gen.	Binding Site	Conformation Targeted¹	T315I Activity	Kinase Selectivity	Key Differentiating Features	Development Status
Mechanism of Action Comparison: BCR::ABL1 TKIs
ATP-competitive and allosteric inhibitors — approved and investigational agents
ATP-Competitive (Active-Site) Inhibitors
Dasatinib	2G	ATP active site	Active & inactive (DFG-in/out); type I/II	No	Broad (SRC, PDGFR, c-KIT, ephrin)	Potent SRC inhibition; CNS penetration; pleural effusion risk	Approved (1L, 2L+)
Nilotinib	2G	ATP active site	Inactive (DFG-out); type II	No	Moderate (PDGFR, c-KIT, DDR1)	Optimized imatinib analogue; cardiovascular risk (PAOD); lipid/glucose effects	Approved (1L, 2L+)
Bosutinib	2G	ATP active site	Active (DFG-in); type I	No	Moderate (SRC, TEC)	Dual SRC/ABL inhibitor; GI toxicity prominent; less CV toxicity	Approved (1L, 2L+)
Ponatinib	3G	ATP active site	Inactive (DFG-out); type II	Yes	Broad (FGFR, VEGFR, PDGFR, SRC, FLT3)	Ethynyl linker spans T315I gatekeeper; AOEs; dose–response for efficacy & safety	Approved (2L+/T315I)
Olverembatinib	3G	ATP active site	Inactive (DFG-out); type II	Yes	Broad (PDGFR, c-KIT, FGFR)	QOD dosing; covers T315I & compound mutations; thrombocytopenia; approved in China	Approved (CN); Phase II/III (global)
Vodobatinib	3G	ATP active site	Inactive (DFG-out); type II	Yes	More selective than ponatinib (reduced FGFR/VEGFR)	Designed for improved selectivity vs ponatinib; combination partner with asciminib	Phase II (VELOCITY)
ELVN-001	3G	ATP active site	Inactive (DFG-out); type II	Yes	Highly selective for ABL1 (minimal FGFR/VEGFR)	T315I coverage with reduced off-target kinase activity; potentially lower vascular risk	Phase I/II
Allosteric (Myristoyl Pocket / STAMP) Inhibitors
Asciminib	—	Myristoyl pocket	Induces inactive closed conformation	Yes (200 mg BID)²	Highly selective for BCR::ABL1	First-in-class STAMP inhibitor; combinable with ATP-site TKIs; myristoyl pocket mutations (A337V, P465S, V468F, I502L) confer resistance	Approved (3L+, T315I); Phase III 1L
TGRX-678	—	Myristoyl pocket	Induces inactive closed conformation	Yes	Highly selective for BCR::ABL1	Next-gen STAMP; reported activity against some asciminib-resistant mutations; QD dosing	Phase I/II (China-led)
TERN-701	—	Myristoyl pocket	Induces inactive closed conformation	Yes	Highly selective — 0/468 kinase interactions³	Next-gen STAMP; superior potency vs asciminib on M244V & F359 mutations; QD dosing; Cave at 320/500 mg exceeds IC90 for most variants; P-gp inhibitor; no clinically relevant CYP interactions⁴	Phase I (CARDINAL)
¹ STAMP = Specifically Targeting the ABL Myristoyl Pocket; DFG = Asp-Phe-Gly motif.
² Asciminib T315I activity requires higher dose (200 mg BID vs 80 mg QD for non-T315I).
³ TERN-701 selectivity: 468 kinase assays tested, 0 significant interactions mapped (Parsons et al., EHA 2025).
⁴ DDI profile: P-gp inhibitor; not a clinically relevant inhibitor of CYP3A4, CYP2C8, CYP2C19, or OATP1B1/3 (Anderson et al., SOHO 2025, Poster CML-586).
Sources: Anderson et al., SOHO 2025 Poster CML-586; Parsons et al., EHA 2025 (s425); product prescribing information; ClinicalTrials.gov.
Abbreviations: 1L = first-line; 2G/3G = second/third generation; AOE = arterial occlusive event; BID = twice daily; Cave = average concentration; CN = China; CV = cardiovascular; GI = gastrointestinal; QD = once daily; QOD = every other day; VEGFR = vascular endothelial growth factor receptor.

Mechanistic Implications for Sequencing

ATP-competitive → Allosteric: Non-overlapping binding sites allow combination strategies (e.g., asciminib + ATP-site TKI) and rational sequencing after ATP-site TKI failure, as resistance mutations in the active site do not affect allosteric binding.

Allosteric → Allosteric: Myristoyl pocket mutations (A337V, P465S, V468F, I502L) that emerge on asciminib may show differential sensitivity to next-generation STAMP inhibitors. TERN-701 preclinical data demonstrate superior potency vs asciminib against F359C/I/V and M244V mutations, suggesting potential utility in the post-asciminib setting.

T315I considerations: All 3G ATP-competitive inhibitors and all allosteric inhibitors cover T315I, but through distinct mechanisms — offering multiple options and potential combinations for this historically challenging mutation.