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Overcoming multidrug resistance

Name of the project

Development of technology for overcoming multidrug resistance based on inhibition of cellular ABC efflux transporters

Key idea (slogan) of the project

Overcoming multidrug resistance

Partner organization

– I.M. Sechenov First Moscow State Medical University

– Volgograd State Medical University

– Saint-Petersburg State Chemical Pharmaceutical Academy

– Institute of physiologically active compounds, Russian Academy of Sciences (Chernogolovka)

– University of Atlanta (Atlanta, USA)

– JSC “Tatkhimpharmpreparaty”

Global scientific/technological goal (challenge) of the project

Pathological cells possess well developed mechanisms of multidrug resistance (MDR) that seriously limit the efficacy of drugs. The key mechanism of drug resistance is the overexpression of ATP-binding cassette (ABC) efflux transporters, which remove drug molecules from the intracellular space. It was shown that the effective inhibitors of ABC efflux transporters can overcome MDR but most of these agents are toxic. Thus the design of new inhibitors remains a highly actual problem.

Academic supervisor of the project

Gjumrakch Aliev (h-index 40)

Description of the project

1. Pathological cells possess well developed mechanisms of multidrug resistance (MDR) that seriously limit the prolonged and effective use of chemotherapeutic drugs. The key mechanism of drug resistance is related to activity of ATP-binding cassette (ABC) efflux transporters, which effectively remove xenobiotics, including drug molecules, from the intracellular space. For example, this mechanism is employed by cancer cells and hampers the success of cancer pharmacotherapy. 2. Previous studies clearly demonstrate that the effective inhibitors of ABC efflux transporters can overcome MDR, but the clinical trials have shown that most of these agents are toxic and only show limited or no benefits to patients. Thus, the design of new inhibitors remains a highly actual but still unsolved problem. 3. The project initiators have discovered an innovative, previously unknown type of ABC efflux transporter inhibitors based on unique chiral supramolecular conjugates (CSC). Application of CSC in combination with a chemotherapeutic drug significantly potentiates the drug’s activity. Implementation of such CSCs paves the way to a wide number of efficient drug combinations based on the well-known pharmaceutical substances, for the treatment of many socially important diseases.

4. In particular, at the developmental stages of the project, the members of the project consortium are planning to develop a number of such drug combinations for the treatment of cancer, inflammatory and CNS diseases. 5. The project can be considered an innovative, high-tech study in the field of drug design and discovery. It is based on modern research equipment and technologies including genomics, proteomics, electronic microscopy, complex chemo- and bioanalytical systems, etc. The discovered class of ABC transporter inhibitors represents a novel, unique type of noncovalent chiral supramolecular conjugates (CSC) which can selectively and effectively interact with the extracellular domains of the transporters.

The following specific results will be achieved:

A. The collaborators will obtain in-depth knowledge of mechanisms of ABC efflux transporter inhibition by CSC in various cells and in vivo models for more efficient discovery of novel CSC-drug combinations.

B. A finished drug formulation of CSC will be developed and standardized for further preclinical and clinical studies.

C. A finished drug formulation of CSC will be developed and standardized for further preclinical and clinical studies.

Approaches to the implementation of the project

Key approaches and technologies in the project: 1. Genome and proteome studies on cell models. 2. Studies of membrane effects on model and natural biomembranes. 3. Efficacy and safety studies on in vivo models corresponding on specific pathologies. 4. Chemical technology development.

University’s experience, research and technological preliminary preparatory work

1. KFU and, in particular, its specialized research and educational centers, the Scientific and Education Center of Pharmaceutics (SECP) and the Butlerov Chemical Institute (BCI), possess well developed research capacities and unique competences in the field of drug discovery and development. In the recent years, these centers have developed a number of promising molecules in the exploratory and preclinical stages including several drug candidates which are now under active preclinical development in the framework of the Federal Targeted Program Pharma-2020. 2. SECP and BCI have modern scientific equipment and first-rate competences in the exploratory and preclinical stages of drug discovery and development. The suggested scientific collaborators will harmonically supplement these competences. 3. To this date, the project initiators have successful results in the design of ABC efflux transport inhibitors. These results were subjected to careful internal and external expert’s examination. Now the approach is successfully validated in the design of anticancer and anti-inflammatory drugs. All the information related to these inhibitors (formulae, designs, drawings, procedures and methods) is unpatented yet and confidential (know-how). 4. The unique advantages of KFU as the project initiator are related to several factors: a) rich traditions of the Kazan school of organic and medicinal chemistry; b) modern high-tech research infrastructure and highly skilled personnel of SECP – the leading research center in RF established in the framework of the Federal Targeted Program Pharma-2020; c) highly complementary competences of the suggested scientific collaborators, which represent the leading research centers working in the field of drug discovery; d) unique, advanced nature and properties of the discovered ABC efflux transporter inhibitors.

Achieving of global leadership (excellence), as one of the project results

1. The global leadership will be achieved in the field of design and development of ABC efflux transporter inhibitors. Despite active international research effort in the field, the problem remains highly actual and yet unsolved. 2. The unique competences will be developed associated with the design of innovative CSC-drug combinations, which will outperform the unmodified drugs in efficacy and safety. 3. The results will be essential, first of all, in anticancer drug development, and then in other therapeutic areas (anti-inflammatory, CNS therapies, etc.): the drug designers will obtain a technology to overcome MDR and, therefore, to radically enhance the efficacy and safety of known drugs without discovery of novel drug molecules.

Significance, relevance and academic novelty of the project

1. The contribution of the project and its results to science is the development of a unique, powerful technology to overcome MDR and, therefore, to radically enhance efficacy and safety of known drugs. 2. In the scientific environment, the results will be visible after the very initial publications demonstrating the observed breakthrough effects related to inhibition of ABC efflux transporters. 3. The project belongs to the field of “Live sciences”, which is included into the list of the priory directions of development of science, technology and technics in Russian Federation (decree of the President of RF, July 07, 2011, #899). The project is also connected to the global challenge related to limited efficacy of many drugs due to activity of ABC efflux transporters. 4. The project novelty is related to discovery of a novel type of chemical agents, the noncovalent chiral supramolecular conjugates (CSC), which do not have own pharmacological activity (or, more truly, the issue remains unclear) but radically enhance efficacy and safety of the existing drug substances (anticancer, anti-inflammatory, etc.). This result is innovative, since all the investigations in the field still did not lead to viable drug candidates.

Relevance and significance of the project in technologies
1. The results of the project can significantly influence the preclinical drug discovery technologies. For example, the experimental studies of the expression and role of ABC efflux transporters in particular pathologies can become essential part of the preclinical phase of drug development. In those cases, where the connection of ABC efflux transporters with MDR effects for particular drugs will be reliably established, the optimal research strategy will involve development of CSC-drug combinations.
2. The indicated technological changes will have a global character.
3. The project results can be implemented in technological processes in very short time, without significant costs compared to the discovery of novel drug substances. Thus, a pilot study of innovative combination of CSC with doxorubicin has been successfully completed; the combination significantly outperforms doxorubicin in anticancer efficacy and safety in in vivo models.
4. 3. The project belongs to the field of “Live sciences”, which is included into the list of the priory directions of development of science, technology and technics in Russian Federation (decree of the President of RF, July 07, 2011, #899). The project is also connected to the global challenge related to limited efficacy of many drugs due to activity of ABC efflux transporters.