Anaplastic Lymphoma Kinase Inhibitors for the Treatment of ALK-Positive Cancers

Kinoshita, Kazutomo; Oikawa, Nobuhiro; Tsukuda, Takuo

doi:10.1016/b978-0-12-396492-2.00019-9

Cited by 13 publications

(9 citation statements)

References 39 publications

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“…The metabolic stability of 1 in human liver microsomes (HLM) and human hepatocytes (hHep) is encouraging and may be high enough to deliver low metabolic clearance (CL) in humans. Also encouraging is the lack of blockade of the human ether-a-go-go related gene (hERG) encoded potassium channel, as demonstrated by the lack of signal in the dofetilide binding assay. , Compound 1 is a weak substrate for the efflux transporter P-gp (efflux ratio (ER) in the MDCK-MDR1 assay = 2.1) is poorly soluble (<0.3 μM at pH 6.5) and has low passive permeability (RRCK A to B apparent permeability ( P app ) = 0.6 × 10 –6 cms –1 ), such that limitations on oral bioavailability may be expected in the absence of formulation enhancement.…”

Section: Resultsmentioning

confidence: 99%

The Discovery of a Potent, Selective, and Peripherally Restricted Pan-Trk Inhibitor (PF-06273340) for the Treatment of Pain

et al. 2016

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The neurotrophin family of growth factors, comprised of nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4), is implicated in the physiology of chronic pain. Given the clinical efficacy of anti-NGF monoclonal antibody (mAb) therapies, there is significant interest in the development of small molecule modulators of neurotrophin activity. Neurotrophins signal through the tropomyosin related kinase (Trk) family of tyrosine kinase receptors, hence Trk kinase inhibition represents a potentially "druggable" point of intervention. To deliver the safety profile required for chronic, nonlife threatening pain indications, highly kinase-selective Trk inhibitors with minimal brain availability are sought. Herein we describe how the use of SBDD, 2D QSAR models, and matched molecular pair data in compound design enabled the delivery of the highly potent, kinase-selective, and peripherally restricted clinical candidate PF-06273340.

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Section: Resultsmentioning

confidence: 99%

The Discovery of a Potent, Selective, and Peripherally Restricted Pan-Trk Inhibitor (PF-06273340) for the Treatment of Pain

et al. 2016

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“…35 In the landscape for c-Met, while earlier inhibitors may have encountered challenges in target potency and selectivity, newer inhibitors will likely be more successful in exploring potential clinical benefit. 36 In this report, we have studied CM-118, a novel aminopyridazine-based inhibitor that targets c-Met and ALK in vitro and in vivo.…”

Section: Discussionmentioning

confidence: 99%

A novel lead compound CM-118

Ли

Shu

Chang

et al. 2014

Cancer Biology & Therapy

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“…The development of secondary kinase mutations clustering around the ATP binding site of the EML4-ALK rearrangement is likely the most important mechanism underling the resistance to crizotinib 10 , 11 , 12 . L1196M and C1156Y were the earliest two secondary ALK mutations conferring resistance to crizotinib identified clinically.…”

Section: First-generation Alk Inhibitor and Its Acquired Resistancementioning

confidence: 99%

Alectinib: a novel second generation anaplastic lymphoma kinase (ALK) inhibitor for overcoming clinically-acquired resistance

Song

Wang

Zhang

2015

Acta Pharmaceutica Sinica B

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The development of inhibitors for the tyrosine anaplastic lymphoma kinase (ALK) has advanced rapidly, driven by biology and medicinal chemistry. The first generation ALK inhibitor crizotinib was granted US FDA approval with only four years of preclinical and clinical testing. Although this drug offers significant clinical benefit to the ALK-positive patients, resistance has been developed through a variety of mechanisms. In addition to ceritinib, alectinib is another second-generation ALK inhibitor launched in 2014 in Japan. This drug has a unique chemical structure bearing a 5H-benzo[b]carbazol-11(6H)-one structural scaffold with an IC50 value of 1.9 nmol/L, and is highly potent against ALK bearing the gatekeeper mutation L1196M with an IC50 of 1.56 nmol/L. In the clinic, alectinib is highly efficacious in treatment of ALK-positive non-small cell lung cancer (NSCLC), and retains potency to combat crizotinib-resistant ALK mutations L1196M, F1174L, R1275Q and C1156Y.

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Anaplastic Lymphoma Kinase Inhibitors for the Treatment of ALK-Positive Cancers

Cited by 13 publications

References 39 publications

The Discovery of a Potent, Selective, and Peripherally Restricted Pan-Trk Inhibitor (PF-06273340) for the Treatment of Pain

The Discovery of a Potent, Selective, and Peripherally Restricted Pan-Trk Inhibitor (PF-06273340) for the Treatment of Pain

A novel lead compound CM-118

Alectinib: a novel second generation anaplastic lymphoma kinase (ALK) inhibitor for overcoming clinically-acquired resistance

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