Crizotinib structure activity relationship

crizotinib structure activity relationship

Conclusions: Ceritinib has activity in crizotinib-resistant and Pei, W, Chen, B. Synthesis, structure-activity relationships, and in vivo efficacy of. In this initial report, preliminary structure–activity relationships (SARs) are .. Ceritinib alone for crizotinib-naive versus crizotinib-pretreated. Crizotinib was the first ALK tyrosine kinase inhibitor licensed for the Synthesis, structure-activity relationships, and in vivo efficacy of the novel.

Most relapses occur within the first year of treatment, although prolonged responses lasting over 6 years can rarely be seen. For the majority of patients, disease progression after treatment with crizotinib will similarly involve multiple sites [ 10 ]. In a smaller proportion of patients, oligoprogression, or progression limited to a few metastatic sites, has been described.

The following sections will review two patterns of progression that have emerged with increased experience with treating patients with crizotinib Figure 1and briefly discuss some early strategies that have been successful in addressing these unique patterns of treatment failure. View large Download slide Diverse mechanisms of resistance leading to systemic relapse can emerge in the setting of selective pressure exerted by crizotinib.

Identified mechanisms of resistance are depicted on the right. Different patterns are seen during progression on crizotinib depicted on the left. Progression typically involves multiple sites. A subgroup of patients will have oligoprogression, or relapse involving only limited sites.

New treatment options for ALK+ advanced non-small-cell lung cancer: critical appraisal of ceritinib

Similarly, in one single-institution study, brain metastases were present in In patients with treated brain metastases enrolled on PROFILEthere was a significant improvement in the intracranial disease control rate DCR and intracranial PFS in those treated with crizotinib compared with those treated with chemotherapy [ 16 ].

Unfortunately, despite significantly improved disease control with crizotinib compared with chemotherapy, central nervous system CNS progression is frequently observed [ 1718 ]. In a retrospective pooled analysis from the PROFILE and trials, median time to intracranial progression among patients with asymptomatic untreated brain metastases was 7 months compared with a The predisposition toward CNS relapse as an initial site of failure has been largely attributed to pharmacokinetic shortcomings of crizotinib.

In particular, crizotinib is a known substrate of P-glycoprotein, a drug efflux pump that limits accumulation of the drug in the CNS [ 2021 ]. ALK fusions have gain of function properties while activating mutations in wild-type ALK can also occur within the tyrosine kinase domain. The basic approaches of any computer aided drug design work in terms of structure and ligand based drug design.

Details of each of these approaches should be covered with an emphasis on utilizing both in order to develop multi-targeted small-molecule kinase inhibitors. Herein, we highlight the importance of targeting these proteins and the advances in optimizing more potent and selective ALK and ROS1 kinase inhibitors. Accepted for publication Mar 25, Conventional chemotherapeutic regimens only marginally improve the outcome of NSCLC patients at advanced stages of disease, with median survival time less than one year after diagnosis 2.

Protein kinase activation by somatic mutation or chromosomal alteration is a common mechanism of tumorigenesis.

The discovery of a number of these molecular alterations underlying lung cancer has led to uniquely targeted therapies with specific inhibitor drugs such as erlotinib and gefitinib for mutations in the epidermal growth factor receptor EGFRor crizotinib for the gene translocation resulting in the echinoderm microtubule associated protein like 4 EML4 -anaplastic lymphoma kinase ALK oncogene 3 - 5. Patients with EML4-ALK positive tumors are characteristically younger age, female, and never to light smokers 589.

crizotinib structure activity relationship

It has been recently reported that approximately 1. Patients with ROS1 rearrangements are also significantly younger, more likely to be never-smokers and are more often diagnosed with the histological subtype of adenocarcinoma with wide distribution of tumor grade Recently, a report from investigators at the Massachusetts General Hospital Cancer Center has showed that ROS1-driven tumors can be treated with crizotinib and describes the remarkable response of one patient to crizotinib treatment This review focuses on the importance of targeting these proteins and describes the advances in optimizing more potent and selective ALK and ROS1 kinase inhibitors that have an optimal pharmacokinetic profile and the capacity to inhibit acquired resistant mutations.

crizotinib structure activity relationship

We aim to stimulate interest and encourage of researchers from different disciplines to learn about new therapeutic avenues following the development of compounds targeting ALK and ROS1 kinases with the aim of increasing survival to these lethal forms of lung cancer. Structural insights and computational simulations Receptor Tyrosine kinases RTK are transmembrane glycoproteins where the domain responsible to the tyrosine kinase activity is located in the cytoplasm.

Although extracellular domain shows remarkable structural differences between TK families, the intracellular region is sensibly conserved.

Although a few years ago there was no resolved three-dimensional structure of ALK, similarity between its sequence permitted to predict its folding from a known RTK structure used as a template, using homology models. Fortunately, recently some crystal structures of the catalytic domain of ALK have been reported in literature at different resolution levels.

Structure has been colored according to its resolution: The loop regions show the main differences between structures Once the three-dimensional structure of the ALK receptor is available, biological processes related to its structure can be studied virtually, as for example substrate affinity 22receptor autoactivation or resistant mutations.

It can even be used as a structural template in order to predict the structure of RTK homologues by homology modeling However, crystallographic data should be taken carefully: Additionally, some ALK molecular structures have also been resolved including a bound ligand Table 1. These co-crystallized structures reveal the active site of the protein against one giving compound and describe the interaction within the protein-ligand complex.

crizotinib structure activity relationship

This information is relevant to assist structure-aided molecular design of ALK inhibitors i. By the time diaminopyrimidine DAP derivatives were consolidated as bioactive motives, great efforts were done in order to increase its selectivity 31to optimize their activity 32 or to propose new scaffolds that mimic them.

Evaluation of receptor-ligand interactions using docking techniques has become the most preferred SBDD method to study small-molecule ALK inhibitors, not only specific compounds as Novartis NVP-TAE 17 but also families including pyridine 33pyrrolotriazine 192-acyliminobenzimidazole 28and tetrahydropyrido-[2,3-b]pyrazine 34 derivatives. Besides specific chemical families, commercial or public chemical libraries can also be screened using docking techniques in order to identify new candidates 18 This helps to identify e.

Met and Glu Structure-Activity Relationship SAR models correlate the chemical structure of inhibitors with their biological activity. They have been applied to screen series of piperidine carboxamides 272-acyliminobenzimidazoles 28macrocycles 367-amino-1,3,4,5-tetrahydrobenzo[b]azepinones 372,3,4,5-tetrahydro-benzo[d]azepines 382,7-disubstituted pyrrolo[2,1-f][1,2,4]triazines 39diaminocyclohexane methanesulfonamides 40 or tetracyclic derivatives 4142tetrahydropyrido[2,3-b]pyrazines 343,5-diamino-1,2,4-triazole ureas 43aryloxy oxo pyrimidinones 44identifying which substituents confer high ALK-response and proposing chemical modifications of hit compounds.

Most of published LBDD studies include modeling of candidates with the receptor using docking. Since mechanisms to drug resistance have been experimentally related to mutations in the ALK amino acid sequence, many efforts have been done in order to obtain resolved crystal structures of ALK mutants Table 2.

Table 2 List of resolved structures of mutated ALK receptor Full Table Ligand co-crystallizations are also available in mutated structures mainly FL and RQ 26highlighting structural changes responsible of such behavior. Although resistance can be well correlated with structural changes in some cases e. Although Lys-Met exchange the binding mode of crizotinib remains unchanged. This knowledge has been used to design new compounds against gatekeeper mutants Figure 3 Graphical representation of key mutations related with ALK resistance However, other mutations have also been identified.

On the basis of the crystal structures, these mutations can be related with formation or alteration of hydrogen bonds e. Thus, ligand co-crystallizations can not only help to the understanding of the structural basis of mutations related to drug resistance, but also to identify the binding mode of the second generation ALK inhibitors When no crystallographic data is available, binding mode of new inhibitors with ALK mutants are computationally modeled using docking techniques 54 or molecular dynamic simulations These interaction models provide a useful tool to screen drug candidates after their validation with experimental evidences.

However, specificity for one receptor could be undesirable in a so complex biological context. For this reason, promiscuous inhibitors e. When a set or library of knowing active ligands for one target is available, the specificity for the second target can be predicted by screening the previous library applying either SBDD or LBDD Homology models can be later used to study molecular interactions with ligands using docking methods in order to elucidate their binding mode In contrast to homology models, other studies consider the structurally related MET receptor as a reference to find inhibitors which are able to interact with kinase domain.

Given the receptor, homology docking studies on MET receptors could be therefore extended to structurally similar receptors like ROS1 The principal reported inhibitors, the companies involved in the development, the core scaffold present in such compounds, the mutation against which the compounds are effective, their off-targets, and the clinical stage achieved are summarized in Table 3.

On the other hand, the structures of the disclosed compounds are included in Figure 4. Despite several studies have reported the effectiveness of NVP-TAE against tumors induced by constitutively active ALK or against cell lines with ALK translocations and point mutations, this compound is not currently in any clinical trial 64 - Crizotinib, with an aminopyridine as a core, was described for first time in and only three years later were reported the first promising clinical trials in NSCLC patients with EML4-ALK fusion genes 5.

Among the patients enrolled, after the treatment with crizotinib, 2 displayed a total recovery, 69 had a partial response and 31 were considered to have stable disease After the clinical trials of crizotinib, ALK was established as a drug target in cases of NSCLC, but the discovery of resistance related to mutations created the need to develop a second-generation of ALK inhibitors with the capability to overcome mutation-mediated drug resistance.

Some pharmaceutical companies and research groups have reported different new promising candidate drugs to inhibit mutated ALK.

Crizotinib | C21H22Cl2FN5O - PubChem

One of these second-generation ALK inhibitors is AP, whose chemical structure has not been disclosed but it is believed to be a member of a family compounds described in a patent of ARIAD based on a diaminopyrimidine structure bearing pendant phosphinoyl groups In this paper, preclinical and clinical data of ceritinib are reviewed, and its role in the clinical setting is put into perspective. In recent years, an improved understanding of the molecular and genetic background of lung cancers has changed treatment paradigms for these patients.

With the detection of activating mutation in EGFR, 23 rearrangements of ALK with EML4 4 and others, a more personalized and targeted therapeutic approach is the standard of care for a subset of patients with lung adenocarcinoma. ALK is a transmembrane tyrosine kinase receptor that is expressed in neural tissue, the small intestine, and the testes, and plays a crucial role in the development of the central nervous system CNS.

The primary end point of progression-free survival PFS was prolonged from 3 months with chemotherapy to 7. Based on these data, crizotinib has been approved in several countries including the USA, most European countries, and Switzerland and is the recommended first-line therapy for ALK-positive patients.

Resistance develops through a variety of mechanisms. Recently, several other secondary mutations have been described. Mainly, the chlorine in the fifth position of the pyrimidine ring enhances interactions of ceritinib with the mutant residues at the gatekeeper position of the ALK kinase domain. Ceritinib is slowly absorbed, with median peak plasma concentration occurring at approximately 4—6 hours in patients and at approximately 6—8 hours in healthy subjects. Following peak concentration in the plasma Cmaxceritinib concentrations declined in a monoexponential manner.

The geometric mean, apparent terminal half-life ranged from 31 to 41 hours across the — mg dose groups in patients, and from 36 to 48 hours across the — mg dose groups in healthy subjects. A food effect study conducted in healthy subjects showed that, following a single mg oral dose of ceritinib, the bioavailability of ceritinib is increased when the dose is given with a meal. In an ongoing open-label, multicenter, randomized, parallel design Phase I study, the systemic exposure and safety of ceritinib administered at or mg with a daily low-fat meal vs mg daily in the fasted state will be determined following multiple oral daily dosing in patients with metastatic ALK-positive NSCLC.

The primary objective of this study is to assess the steady-state pharmacokinetics of or mg ceritinib taken with a low-fat meal as compared with that of mg ceritinib taken in the fasted state in patients with metastatic ALK-positive NSCLC.

Secondary objectives will be to assess the safety and efficacy of ceritinib when administered at or mg with a daily low-fat meal or mg daily in the fasted state. The maximum tolerated dose was mg once daily.

crizotinib structure activity relationship

From this Phase I trial, efficacy data were reported from patients being treated with at least mg ceritinib per day. Interestingly, responses were reported in patients with untreated brain metastases occurring during crizotinib therapy. PFS for patients with brain metastases was not different 6.

crizotinib structure activity relationship

In summary, this Phase I trial with an expansion cohort was able to show promising efficacy data of ceritinib in ALK-positive lung adenocarcinoma. Median age of the cohort was 53 years, with a predominance Approximately, one-fourth of patients were pretreated with one, two, or more than three treatment lines.