The project entitled:

"New kinases of important role in cancer - structural characterization"

funded by National Centre of Science, Poland between 2013 and 2016.

The primary scientific objectives of the proposed research project are: (i) to obtain missing structural information and (ii) to uncover novel specificity determinants of protein kinases having important role in cancer through X-ray crystallographic characterization of apo-forms and complexes with ATP analogues and small molecule inhibitors.

Kinase inhibition is a well established and broadly explored therapeutic strategy for selectively targeting cancer cells. The majority of small-molecule kinase inhibitors developed so far act as ATP competitors. Due to the highly conserved structure of the ATP binding domain in most kinases, these inhibitors often suffer from cross-reactivity with multiple kinases, resulting in poor safety and sometimes severe side effects. Exploring both the ATP binding pocket and the adjacent, less conserved sites for inhibitor design offers the potential of increased selectivity towards particular target kinases. However, the adjacent sites are currently insufficiently defined in multiple pharmaceutically important kinases. Moreover, structural information on some of the kinases of interest is utterly nonexistent. Therefore, the project aims to provide basic knowledge on structural organization of kinases important in cancer for which such information is currently not available and at defining novel specificity determinants (adjacent sites) in direct vicinity of the ATP binding pocket. These aims are going to be realized through detailed structural (X-ray crystallography) characterization of apo-forms of the kinases of interest and their complexes with ATP analogues and first generation small molecular weight inhibitors.

Cancer is the leading cause of death worldwide, accounting for approximately 7.6 million deaths per year according to World Health Organization (Jemal, Bray et al. 2011).

Historically anticancer therapies were characterized by severe side effects and low efficacy. Current, mechanism-based targeted cancer therapy represents a remarkable progress compared to traditional cytotoxic drugs. On average the lifespan and quality of life of cancer patients improved substantially and currently cancer is not necessarily a death sentence. Nonetheless, despite dynamic development, medicine all too often remains helpless in the struggle against neoplasms. It is significant that people who escaped cancer are still called survivors instead of those healed or cured. Therefore, further extensive effort is required to develop yet more effective and safer therapeutic strategies.

Kinase inhibition is a well established and broadly explored therapeutic strategy for selectively targeting cancer cells while sparing normal cells. A number of successful anticancer drugs inhibiting protein kinases had already been approved. Examples include, but are not limited to, lapatinib, nilotinib, gefitinib, crizotinib, axitinib and other. Nonetheless, vast part of the cancer kinome remains relatively poorly explored in this context. In the last decade multiple novel signaling pathways aberrantly regulated in cancer have been characterized. Pharmacological interference in some of those pathways promises potential clinical advantage. However, preclinical progress is often hindered by insufficient basic knowledge including either the details and interconnections of involved signaling pathways or the structural knowledge on potential targets or both. Therefore, a large spectrum of potentially relevant kinases remains pharmaceutically unexplored.

The majority of small-molecule kinase inhibitors developed so far act as ATP competitors targeting the ATP binding site of kinases. Due to the highly conserved structure of the ATP binding pocket in most kinases, first generation ATP mimetic inhibitors of particular kinases often suffer from cross-reactivity with other kinases, resulting in poor safety and sometimes severe side effects. To achieve good selectivity profiles, interactions with non-conserved, kinase specific regions are explored in parallel to the interactions in the ATP binding pocket. A number of ATP competitive inhibitors utilizing both the ATP binding pocket and the adjacent, non-conserved binding sites have been successfully developed as therapeutics (ex. imatinib, nilotinib). However, the design of such inhibitors, targeting pathways yet unexplored in this context, is often hindered by insufficient structural information, especially when emerging, potentially pharmaceutically important kinases are considered. Therefore, the current project focuses on a number of kinases for which convincing in vivo data documenting their involvement in cancer has been provided however, the structural information is unavailable or largely incomplete. The major objective of the project is to provide structural information on kinases relevant in cancer by crystallizing and determining high resolution X-ray structures of apo-forms, nucleotide analogue bound and 1st generation inhibitor bound complexes. Such obtained basic knowledge will strongly substantiate our current understanding of the structural features of selected families of protein kinases and will provide explanation of the molecular basis of inhibitor selectivity / cross-reactivity. In a broader perspective it is likely to facilitate future development of selective inhibitors of the promising kinase targets by uncovering non-conserved binding sites adjacent to ATP binding pocket.

The kinase panel selected for characterization within the current project was carefully chosen based on the following criteria:

(i) the therapeutic potential of targeting particular kinase is relatively well documented in vitro and in animal models;
(ii) structural information concerning the particular kinase is missing or is largely insufficient for structure based inhibitor design;
(iii) the kinase was relatively recently recognized as a suitable therapeutic target (specific inhibitors are developed not further than phase I clinical trials, preferably only in preclinical development or nonexistent).

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