Kinase inhibitors for CNS penetration

The need to develop new brain cancer treatments using targeted molecular therapy was recognised over a decade ago. Glioblastoma—the most common form of malignant primary brain tumour – is the leading cause of cancer death in children and it also accounts for a high proportion of cancer deaths in adults. Currently, there are only two FDA approved chemotherapeutics for the treatment of glioblastoma multiform: the alkylating agents temozolomide and the carmustine-based Gliadel wafer. The success of kinase inhibitors in treating various malignancies suggests that it is highly desirable to identify a kinase inhibitor, capable of effectively crossing the blood-brain barrier (BBB). This necessity also arises from the risk factor when metastasis of tumour to the central nervous system (CNS) occurs as a mechanism of emergent resistance, if the inhibitor does not freely penetrate CNS.

While the importance of free BBB penetration for drugs targeting brain cancer is well understood, it is also essential to correctly assess the extent of this BBB penetration (as opposed to just achieving a target free concentration in the brain), for which a comparison of free brain concentrations to free plasma concentrations is needed (Kp,uu). The values of <0.1 are considered to be low (limited CNS penetration), whereas the values of >0.3 demonstrate a significant degree of free BBB penetration. The principal requirement for any small molecules to achieve the adequate Kp,uu values is that the molecules are not the substrates of the efflux transporters, such as P-gp or Bcrp, which are highly expressed at the BBB interface, and to possess the required for BBB permeability physicochemical properties. These properties for the CNS drug design have been well reviewed and summarised by Zoran Rankovic, the most critical being the topological polar surface area (TPSA) of the molecule and the number of hydrogen bond donors (HBDs).

In the recent review on kinase inhibitors for the treatment of brain cancer, Tim Heffron has analysed known small molecule kinase inhibitors with reported CNS penetration data and compared their physicochemical properties with those of the approved CNS drugs. Typically, the kinase inhibitors utilise multiple hydrogen bond interactions to achieve effective binding to the catalytic site of a kinase. As the result, the median TPSA values for the approved kinase inhibitors are double of that of the approved CNS drugs (Table 1). Interestingly, for two categories of kinase inhibitors, the first – with limited brain penetration and the other – with evident CNS penetration, there is remarkable similarity in the median values of cLogP, cLogD7.4, TPSA, HBD, and MW. The only notable difference was in the calculated pKa median values, where CNS penetrating kinase inhibitors have a lower median pKa than either kinase inhibitors that do not cross the BBB or CNS drugs.


Table 1. Comparison of median values of physicochemical properties for kinase inhibitors that are reported or predicted (based on efflux transport data) to have limited CNS penetration or reported to have significant free CNS penetration and/or no significant P-gp or Bcrp efflux.

It is worth noting that the quality of the data set for this comparison and, therefore, additional differentiation in the properties between the groups might be affected by a lack of data on free-brain-to-free-plasma drug concentration ratios (Kp,uu) for most molecules. In addition, there are limitations to the use of calculated physical properties that might conceal actual differences between molecules, and a potential for species differences to affect the interpretation of reported data for P-gp efflux.

Besides, the common medchem strategies to improve CNS penetration and to reduce efflux transport, such as utilisation of intramolecular hydrogen bonds to effectively mask HBDs and reduction in number of rotatable bonds, would not be accounted for in the calculated properties of those molecules.

The research into CNS penetrant kinase inhibitors is a fairly new direction, and to date only a few kinase inhibitors have been reported that are designed to be BBB permeable. This demonstrates that success in this area can be achieved, even if the physicochemical properties of kinase inhibitors and those of CNS drugs at first appear at odds. Of course, many additional variables impact evaluation of CNS penetrant kinase inhibitors clinically (e.g., PK, selectivity profile, safety, extent of free brain penetration, etc.). However, the significant unmet medical need for such inhibitors and the appreciation for what constitutes meaningful (free) brain penetration are driving the current R&D efforts in the discovery of kinase inhibitors for the treatment of brain cancer.

Blog written by Irina Chuckowree


Practical recommendations – virtual screening hit selection and optimisation based on a literature analysis

Virtual screening is a part of modern drug discovery and has received much attention in the literature. The publications to date however largely focus on case studies or descriptions of methodologies and there are no reported views or guidelines on hit selection or optimisation critieria which exist for conventional screening. A recent publication (Zhu et al – Hit Identification and Optimization in Virtual Screening: Practical Recommendations Based on a Critical Literature Analysis ) highlights this issue and seeks to address the gap based upon a thorough review of the literature from 2007 to 2011.

The groups finding are interesting and their conclusions valuable to the practising medicinal chemist.

They found that whilst potency criteria varied the majority of groups employed potency cut offs in the low to mid micromolar range(1-100uM) similar to groups engaged in hit identification via conventional HTS.Another perhaps more disturbing trend observed was that groups were not using physicochemical filters or structural alerts as widely as might expected And they recommend the inclusion of ligand efficiency criteria and application of a structural alert filter.This observation is perhaps some what surprising given the number of recent publications highlighting the dangers of high lipophilicity etc and it would seem that too many chemists are still being seduced by potency and ignoring other important considerations. Another interesting observation is that typical hit rates for virtual screens are highly than those for high throughput screens.

The authors conclude by making some simple and logical recommendations for workers to use in association with future virtual screening campaigns amongst them they emphasise the need to include physico – chemical property filters and further qualify this by pointing out that certain newer target classes may require higher molecular weight ligands