Entrectinib Chemical Properties

Boiling point:

717.5±60.0 °C(Predicted)

Density 

1.340±0.06 g/cm3(Predicted)

storage temp. 

Store at -20°C

solubility 

≥28.05 mg/mL in DMSO; insoluble in H2O; ≥9.82 mg/mL in EtOH with ultrasonic

form 

solid

pka

12.01±0.43(Predicted)

InChI

InChI=1S/C31H34F2N6O2/c1-38-8-10-39(11-9-38)25-3-4-26(29(19-25)34-24-6-12-41-13-7-24)31(40)35-30-27-17-20(2-5-28(27)36-37-30)14-21-15-22(32)18-23(33)16-21/h2-5,15-19,24,34H,6-14H2,1H3,(H2,35,36,37,40)

InChIKey

HAYYBYPASCDWEQ-UHFFFAOYSA-N

SMILES

C(NC1C2=C(NN=1)C=CC(CC1=CC(F)=CC(F)=C1)=C2)(=O)C1=CC=C(N2CCN(C)CC2)C=C1NC1CCOCC1

Entrectinib Usage And Synthesis

Description

Entrectinib is used to treat metastatic (lung cancer that has already spread) non-small cell lung cancer (NSCLC) that is caused by a gene called ROS1. This medicine is also used to treat solid tumors (cancer) that are caused by certain abnormal NTRK genes and have spread or if surgery to remove the cancer is likely to cause severe complications, and there is no acceptable treatment option or the cancer grew or spread on other treatments.

Effect and benefit

Entrectinib belongs to the group of medicines called antineoplastics (cancer medicines). It works by interfering with the growth of cancer cells, which are eventually destroyed.

Mechanism of action

An inhibitor of tropomyosin receptor tyrosine kinases (TRKs) TRKA, TRKB, and TRKC (encoded by the neurotrophic tyrosine receptor kinase [NTRK] genes NTRK1, NTRK2, and NTRK3, respectively), proto-oncogene tyrosine-protein kinase ROS1 (ROS1), and anaplastic lymphoma kinase (ALK); also, inhibits JAK2 and TNK2. Major active metabolite of entrectinib, M5, showed similar in vitro activity against TRK, ROS1, and ALK. Fusion proteins that include TRK, ROS1, or ALK kinase domains can drive tumorigenic potential through hyperactivation of downstream signaling pathways, leading to unconstrained cell proliferation.

Safety

Entrectinib exhibits hepatic metabolism through cytochrome P450 (CYP) 3A and therefore interacts with moderate-strong CYP3A inhibitors and inducers. In addition, due to its effects on the QTcF interval, use of entrectinib should be avoided with other drugs known to prolong the QT/QTc interval.

Pharmacology

Entrectinib, is a weak P-gp substrate that can sustain CNS exposure based on our novel in vitro and in vivo experiments. This is consistent with the observed preclinical and clinical efficacy of entrectinib in neurotrophic tropomyosin receptor kinase (NTRK) and ROS1 fusion-positive CNS tumors and secondary CNS metastases.

Description

Entrectinib (RXDX-101, Ignyta Pharmaceuticals, San Diego, CA, USA) is a small molecule that inhibits the tyrosine kinases TRKA/B/C, ROS1, and ALK (Table?1). It has a preclinical median inhibitory concentration (IC50) of 7?nm against ROS1, higher than crizotinib [95, 96]. Entrectinib was specifically designed to cross the blood-brain barrier [95].

Description

Entrectinib is an inhibitor of TrkA (IC₅₀ = 1.7 nM), TrkB (IC₅₀ = 0.1 nM), and TrkC (IC₅₀ = 0.1 nM), as well as C-ros oncogene 1 (ROS1; IC₅₀ = 0.2 nM) and anaplastic lymphoma kinase (ALK; IC₅₀ = 1.6 nM). Entrectinib blocks proliferation of ALK-dependent cell lines, including those with L1196M or C1156Y resistance mutations, and inhibits ALK‐dependent signaling. It has been shown to inhibit the growth of a non-small cell lung cancer cell line bearing an EML4-ALK rearrangement. In mice bearing various Trk, ROS1, or ALK-driven xenografts, entrectinib has been shown to induce tumor regression.

Uses

Entrectinib, also known as RXDX-101 and NMS-E628, is an oral small molecule inhibitor of TrkA, TrkB and TrkC, as well as ROS1 and ALK, with high potency and selectivity. RXDX-101 has demonstrated potent pharmacological activity in preclinical studies and has the potential to be first-in-class against the Trk family of kinases. PXDX-101 has been well tolerated in patients with advanced solid tumors. PXDX-101 is currently in clinical trials, and is being developed by Ignyta.

Clinical Use

Entrectinib demonstrated potent antitumor effects in tumor cell lines and patient-derived xenograft (PDX) tumor models in preclinical studies. Furthermore, entrectinib can cross the blood–brain barrier (BBB) to impact primary brain tumors and brain metastases in patients with NTRK1/ NTRK2/NTRK3, ROS1, and ALK fusion-driven cancers.

in vitro

entrectinib potently and selectively inhibits the in vitro growth of alk-driven tumors, with confirmed mechanism of action [1].

in vivo

since entrectinib is able to pass the blood-brain barrier, the compound was also tested for efficacy in an xenograft model with alk positive nsclc tumors. mri imaging demonstrated that entrectinib was able to effectively and control the growth of these intracranial tumors dose-dependently, leading to increased survival [1].

References

[1] elena ardini, maria menichincheri, patrizia banfi, daniele casero, m. laura giorgini, m. beatrice saccardo, nadia amboldi, nilla avanzi, paolo orsini, antonella isacchi, enrico pesenti, arturo galvani. the alk inhibitor nms-e628 also potently inhibits ros1 and induces tumor regression in ros-driven models. [abstract]. in: proceedings of the 104th annual meeting of the american association for cancer research; 2013 apr 6-10; washington, dc. philadelphia (pa): aacr; cancer res 2013;73(8 suppl):abstract nr 2092. doi:10.1158/1538-7445.am2013-2092

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