Abstract 2198: PBI-200: A novel, brain penetrant, next generation pan-TRK kinase inhibitor
Bibliographic record
Abstract
Abstract Fusions of NTRK 1, 2 and3 genes encoding the TRK family of receptor tyrosine kinases (TrkA, B and C, respectively) have been reported in 1-3% of all human cancers including lung and breast cancers. NTRK gene fusions are also reported in lung and breast tumors metastatic to the brain as well as in primary brain tumors including glioblastoma (3%), astrocytoma (3%) and pediatric glioma (40%). These gene fusions result in constitutive TRK kinase activity and act as oncogenic drivers of disease. First generation TRK kinase inhibitors have demonstrated clinical proof of concept in patients with tumors bearing NTRK gene fusions. PBI-200 is a novel, selective pan-TRK kinase inhibitor. In biochemical assays it inhibits TrkA, B and C with IC50 values of 0.45, 2.2 and 1.9 nM, respectively. This molecule is highly selective against a panel of 122 other protein kinases tested with the exception of Ros1 (IC50= 31 nM). Importantly, PBI-200 retains potency against resistance mutations reported in patients receiving first generation TRK kinase inhibitors. Biochemical IC50 values are 3.4 nM for the TrkA G595R gatekeeper mutation and 10 nM for the TrkA G667C mutant. PBI-200 potently inhibits proliferation of human tumor cell lines expressing TRK fusions including the KM-12 colorectal cancer cell line (TPM3-NTRK1 fusion; EC50 value = 22 nM) and the MO-91 acute myeloid leukemia cell line (ETV6-NTRK3 fusion; EC50 value = 3.5 nM). It also potently inhibits proliferation of rat BaF3 cells expressing oncogenic NTRK fusions and their resistant variants. In a subcutaneous xenograft model of KM-12 colorectal cancer, PBI-200 induces tumor stasis when dosed intraperitoneally at 15 or 30 mg/kg twice daily (93 and 100% tumor growth inhibition, respectively). The activity of PBI-200 was comparable or superior to that seen with the first generation TRK kinase inhibitors used as comparators in this model. PBI-200 has oral bioavailability in both rat and mouse. Importantly, PBI-200 demonstrates excellent brain penetration in rodent species, with brain/plasma AUC ratios of 3.9 in the mouse and 3.2 in the rat. This is in contrast to the poor brain penetration observed with the first generation TRK kinase inhibitors, larotrectinib and entrectinib.PBI-200 is efficacious in an intracranial KM-12 xenograft model when dosed intraperitoneally or orally, significantly slowing tumor growth and extending survival. Based on the activity of PBI-200 against clinically-relevant resistance mutations and its excellent brain penetration, this molecule has potential to be a next-generation TRK kinase inhibitor especially for primary brain tumors or brain metastatic lesions that harbor a NTRK gene fusion. PBI-200 is currently undergoing further characterization in IND enabling studies. Citation Format: Anthony Regina, Aram Elagoz, Vincent Albert, Jonathan Boudreault, Hong Wang, Marc Ouellet, Nicolas Brunei-Latour, Edith Bellavance, Peter White, Stephane Ciblat, W. Robert Bishop, Kollol Pal. PBI-200: A novel, brain penetrant, next generation pan-TRK kinase inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2198.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.002 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".