INTEGRATING INTERDISCIPLINARY RESEARCH APPROACHES IN DRUG DESIGN AND DEVELOPMENT TO TACKLE BREAST CANCER

Project leaders

Clemente Capasso, Eldehna Wagdy

Agreement

EGITTO - ASRT - Academy of Scientific Research and Technology

Call

CNR/ASRT biennio 2018-2019 2018-2019

Department

Biology, agriculture and food sciences

Thematic area

Biology, agriculture and food sciences

Status of the project

New

Report for renewal

asrt-cnr-2017.pdf

Research proposal

It is worth noting that breast cancer in Egypt is the most commonly diagnosed cancer and the leading cause of cancer death in women. This urgent necessity to fight the breast cancer motivated us to search for novel treatments targeting tumor associated carbonic anhydrase isoforms hCA IX and XII as a novel approach for breast cancer therapy. Whereas, several studies revealed the overexpression of CA IX and CA XII in breast cancer, therapeutic strategies based on the inhibition of CA IX and CA XII have stood out as an auspicious tactic for discovering therapies for human breast malignancy.
Recently, incorporation of urea functionality emerged as the most promising trend in the design of CAIs with good selectivity profile for inhibition of the transmembrane, tumor associated isoforms (CAs IX & XII) over the off-target cytosolic CAs I and II. SLC-0111, an ureido benzenesulfonamide derivative, is currently in clinical evaluations for treatment of breast cancer. In 2016, we developed novel series of ureidosubstituted benzenesulfonamides incorporating isatin moieties which displayed good selectivity profile for the tumor associated isoforms CAs IX (KIs: 5-240 nM) and XII (KIs: 0.47-2.83 nM).
In this proposal, we adopted two strategies to design and synthesize two novel series of carbonic anhydrase inhibitors; (1) Bioisosteric replacement phenyl ring of SLC-0111 with another heteroaryl rings such as pyridine, indole, etc.. (2) Ring expansion approach of the indole moiety, of our recently reported and promising ureido-benzenesulfonamides, to a quinolie moiety. The newly synthesized sulfonamides will be in vitro evaluated for their inhibitory activity against a panel of hCA I, II, and IX isoforms, using an applied Photophysics stopped-flow instrument. Then, the most active derivatives with good selectivity profile for inhibition of the tumor associated isoforms will be examined for their anti-proliferative activity and apoptotic induction potential against breast cancer cell line. Furthermore, a molecular docking of the tested compounds will be carried out in order to investigate their binding pattern with the carbonic anhydrase isoforms CAs IX. Also, the physicochemical properties and ADME profiling for all the synthesized compounds will be performed using Discovery Studio 2.5 (Accelrys, San Diego, CA, USA). In summary, the prime goal is to develop novel sulfonamides with potent and effective anti-proliferative activity towards breast cancer cells targeting tumor associated carbonic anhydrase isoforms CAs IX.

Research goals

We proposed a bilateral research proposal between ASRT of Egypt with CNR of Italy that uses a multidisciplinary team of medicinal, organic, computational chemistry, and molecular biologists to follow these objectives:
1. Design and synthesis of the targeted heteroaryl- and quinazoline-based sulfonamides (about 30 novel compounds) using convenient chemical reactions. As well as Purification of the synthesized compounds.
2. Verification of the structures of the synthesized derivatives using spectral and elemental methods of analysis.
3. Biological Evaluation of the inhibitory activity of the synthesized sulfonamides against the cytosolic carbonic anhydrase isoforms (CAs I and II) and tumor associated (CAs IX and XII).
4. Investigation of the possible binding pattern of the tested compounds with carbonic anhydrase isoforms CAs IX and XII, through carrying out a molecular docking study.
5. Prediction of several ADME descriptors for the synthesized compounds via a theoretical computational kinetic study, using the Discovery Studio 2.5 software (Accelrys, San Diego, CA, USA).
6. Evaluation of anti-proliferative activity of the most potent CAs IX and XII inhibitors against breast cancer cell lines.
7. Apoptosis Study; determination of the relative levels of 35 human apoptosis-related proteins.
8. Data analysis, evaluation of the biological data of the synthesized compounds, and finally documentation of the analyzed data.

Last update: 19/06/2025