Initial Characterization and Toxicology of an Nmt Inhibitor in Development for Hematologic Malignancies
Notice bibliographique
Résumé
N-myristoylation, the addition of the 14-carbon fatty acid to proteins, plays a fundamental role in cell signaling. Over 200 proteins are myristoylated, including the Src Family Kinases (SFK) Src, Lyn, Lck, Hck, and Fgr, as well as c-Abl, Gα subunits, caspase truncated (ct-) Bid and ct-PAK2, regulating cell growth and apoptosis. Human myristoylation is performed by two ubiquitously expressed N-myristoyl-transferases NMT1 and NMT2. PCLX-001 is a new, orally bioavailable, small-molecule, dual NMT inhibitor that is under investigation as a novel and selective treatment for B-cell malignancies. In vitro, PCLX-001 inhibits NMT1 and NMT2 at IC50 of 5nM and 8nM, respectively, inhibits the growth of hematological cancer cells at concentrations 10-fold lower than dasatinib and ibrutinib, and inhibits SFK recruitment to B cell receptor signaling, reducing survival signals and triggering apoptosis. PCLX-001 causes complete tumor regression in NOD/SCID mouse xenograft models of Acute Myeloid Leukemia (AML), Burkitts Lymphoma (BL), and Diffuse Large B-cell Lymphoma (DLBCL), including drug-resistant human tumor in a PDX model. When screened in vitro for its ability to inhibit the activity of 468 kinases and kinase mutants in a KINOMEscan®, PCLX-001 did not inhibit any kinase at up to 10 µM (5380 ng/mL) and produced modest inhibition of only three kinases (MRCKA, PIP5K2B, and SRPK1) at 100 µM (53800 ng/mL). Male rats tolerated single oral doses of PCLX-001 at 100 mg/kg without clear effects, but one of three rats died after a single dose at 1000 mg/kg. Dogs tolerated single oral doses of PCLX-001 at 10 mg/kg without effects, but both dogs showed emesis and diarrhea and lost weight after a single dose at 50 mg/kg. In 21-day xenograft efficacy studies in mice, the maximum tolerated dose level (MTD) was 50mg/kg, which also produced complete tumor remission of most xenografts. Administered daily, the 14-day MTD is >75mg/kg (highest dose tested) in rats and between 5 and 25mg/kg in dogs. The dose-limiting toxicities in dogs involved the gastrointestinal tract and hematopoietic bone marrow. When administered orally, PCLX-001 is 26% bioavailable in rats and >90% bioavailable in mice and dogs. The plasma half-life was 5.7h in mice, 1-2h in rats, and 3.9h in dogs. With repeated daily administration, systemic exposure did not change in dogs but decreased in rats. Based on KINOMEscan® results, PCLX-001 is very unlikely to produce adverse effects in patients due to off-target kinase inhibition. The oral bioavailability and half-life in mice and dogs are consistent with a once-a-day dosing regimen. Repeat dosing studies of up to 21 days in mice and 14 days in rats and dogs determined preliminary MTDs. When extrapolated to human doses based on a body surface area scaling, these MTDs are equivalent to 150mg/m2 in mice, >450mg/m2 in rats, and between 100 and 500 mg/m2 in dogs. These results are consistent with a therapeutic window with potential for tumor response in humans, and support proceeding with 28-day GLP toxicology studies and an IND filing for first in human testing of oral PCLX-001. Disclosures Weickert: Pacylex Pharmaceuticals, Inc.,: Employment. Mackey:Pacylex Pharmaceuticals Inc.: Equity Ownership, Patents & Royalties; illumiSonics Inc: Equity Ownership, Other: Director Role; Pfizer Canada: Honoraria; CME: Honoraria; SMHeartCard Inc: Equity Ownership, Other: Director Role. Berthiaume:Pacylex Pharmaceuticals, Inc.,: Equity Ownership, Patents & Royalties.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».