---
title: "Dual A2AR/EGFR‑targeting thiazolyl‑pyrazoline hybrids for restoring apoptosis in colorectal cancer"
id: "pubmed-42155202"
canonical_url: "https://medichelpline.com/clinical-feed/pubmed-42155202"
content_type: "clinical_feed_article"
specialty: "Oncology"
source_name: "PubMed / NCBI"
source_url: "https://pubmed.ncbi.nlm.nih.gov/42155202/"
doi: "10.1016/j.bioorg.2026.109985"
published_at: "2026-09-05T00:00:00.000Z"
evidence_level: "Journal Article"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Dual A2AR/EGFR‑targeting thiazolyl‑pyrazoline hybrids for restoring apoptosis in colorectal cancer
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/pubmed-42155202
- **Specialty:** [Oncology](https://medichelpline.com/clinical-feed/oncology.md)
- **Primary Source:** PubMed / NCBI
- **Source URL:** [Original Journal Publication](https://pubmed.ncbi.nlm.nih.gov/42155202/)
- **DOI:** [10.1016/j.bioorg.2026.109985](https://doi.org/10.1016%2Fj.bioorg.2026.109985)
- **Published At:** 2026-09-05T00:00:00.000Z
- **Evidence Rating:** Journal Article
## Executive GIST (TL;DR)
- The study developed novel **thiazolyl‑pyrazoline** hybrids designed as dual inhibitors of the **Adenosine A2A receptor (A2AR)** and **Epidermal Growth Factor Receptor (EGFR)** to address therapeutic limitations in colorectal cancer (CRC). - A molecular hybridization approach combined pharmacophores from Gefitinib and Tozadenant to create three chemical series, which underwent molecular docking and iterative biological testing. - Two lead compounds, **6aii** and **10b**, showed potent cytotoxicity against Caco2 colorectal cancer cells with IC50 values of 0.037 ± 0.10 μM and 0.6125 ± 0.13 μM, respectively. - Enzyme inhibition assays demonstrated low‑to‑submicromolar activity against EGFR and A2AR (EGFR IC50 range reported 1.53 ± 0.12 to 8.37 ± 0.03 μM; A2AR IC50 range reported 0.037 ± 0.21 to 0.6125 ± 0.15 μM). - Mechanistic studies indicated induction of S and G2/M cell cycle arrest and modulation of apoptotic gene expression: upregulation of pro‑apoptotic genes **Caspase‑3, TP53, Bax** and downregulation of the anti‑apoptotic gene **Bcl‑2**. - Compound 6ii (noted in abstract) produced the lowest intracellular cAMP levels, supporting suppression of **A2AR** downstream signaling. - In vivo validation using the azoxymethane (AOM)‑induced CRC mouse model showed restoration of colonic crypt architecture, suppression of EGFR overexpression, and acceptable liver serum enzyme safety profiles. - The authors conclude these dual‑targeting hybrids provide a preclinical framework for multi‑target drug discovery in advanced CRC. Specific experimental details (full synthetic routes, complete structure‑activity relationship tables, statistical methods, group sizes, dosing regimens) were not reported in the PubMed abstract and would require consultation of the full text.
## Clinical Analysis & Structured Key Points
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Epub 2026 May 12. # Development of dual A2AR/EGFR targeting pyrazoline-thiazole hybrids for restored apoptotic balance in colorectal cancer [Noura Z Elzoghbi](https://pubmed.ncbi.nlm.nih.gov/?term=Elzoghbi+NZ&cauthor_id=42155202)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42155202/#full-view-affiliation-1 "Department of Medicinal Chemistry, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt.. Electronic address: nora.014170@pharm.suez.edu.eg."), [Safaa M Kishk](https://pubmed.ncbi.nlm.nih.gov/?term=Kishk+SM&cauthor_id=42155202)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42155202/#full-view-affiliation-2 "Department of Medicinal Chemistry, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt.. Electronic address: safaa_keshk@pharm.suez.edu.eg."), [Ashraf H Abadi](https://pubmed.ncbi.nlm.nih.gov/?term=Abadi+AH&cauthor_id=42155202)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42155202/#full-view-affiliation-3 "Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt. Electronic address: ashraf.abadi@guc.edu.eg."), [Ismail Salama](https://pubmed.ncbi.nlm.nih.gov/?term=Salama+I&cauthor_id=42155202)[ 4 ](https://pubmed.ncbi.nlm.nih.gov/42155202/#full-view-affiliation-4 "Department of Medicinal Chemistry, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt.. Electronic address: ismail_mohamed@pharm.suez.edu.eg."), [Khaled M Darwish](https://pubmed.ncbi.nlm.nih.gov/?term=Darwish+KM&cauthor_id=42155202)[ 5 ](https://pubmed.ncbi.nlm.nih.gov/42155202/#full-view-affiliation-5 "Department of Medicinal Chemistry, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt.; Department of Medicinal Chemistry, Faculty of Pharmacy, Galala University, New Galala 43713, Egypt. Electronic address: khaled.darwish@gu.edu.eg.") Affiliations Expand ### Affiliations * 1 Department of Medicinal Chemistry, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt.. Electronic address: nora.014170@pharm.suez.edu.eg. * 2 Department of Medicinal Chemistry, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt.. Electronic address: safaa_keshk@pharm.suez.edu.eg. * 3 Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt. Electronic address: ashraf.abadi@guc.edu.eg. * 4 Department of Medicinal Chemistry, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt.. Electronic address: ismail_mohamed@pharm.suez.edu.eg. * 5 Department of Medicinal Chemistry, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt.; Department of Medicinal Chemistry, Faculty of Pharmacy, Galala University, New Galala 43713, Egypt. Electronic address: khaled.darwish@gu.edu.eg. * PMID: **42155202** * DOI: [ 10.1016/j.bioorg.2026.109985 ](https://doi.org/10.1016/j.bioorg.2026.109985) Item in Clipboard # Development of dual A2AR/EGFR targeting pyrazoline-thiazole hybrids for restored apoptotic balance in colorectal cancer Noura Z Elzoghbi et al. Bioorg Chem. 2026. Show details Display options Display options Format Abstract PubMed PMID Bioorg Chem Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Bioorg+Chem%22%5Bjour%5D&sort=date&sort_order=desc) * [ Search in NLM Catalog ](https://www.ncbi.nlm.nih.gov/nlmcatalog?term=%22Bioorg+Chem%22%5BTitle+Abbreviation%5D) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42155202/) . 2026 Sep 5:179:109985. doi: 10.1016/j.bioorg.2026.109985. Epub 2026 May 12. ### Authors [Noura Z Elzoghbi](https://pubmed.ncbi.nlm.nih.gov/?term=Elzoghbi+NZ&cauthor_id=42155202)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42155202/#short-view-affiliation-1 "Department of Medicinal Chemistry, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt.. Electronic address: nora.014170@pharm.suez.edu.eg."), [Safaa M Kishk](https://pubmed.ncbi.nlm.nih.gov/?term=Kishk+SM&cauthor_id=42155202)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42155202/#short-view-affiliation-2 "Department of Medicinal Chemistry, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt.. Electronic address: safaa_keshk@pharm.suez.edu.eg."), [Ashraf H Abadi](https://pubmed.ncbi.nlm.nih.gov/?term=Abadi+AH&cauthor_id=42155202)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42155202/#short-view-affiliation-3 "Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt. Electronic address: ashraf.abadi@guc.edu.eg."), [Ismail Salama](https://pubmed.ncbi.nlm.nih.gov/?term=Salama+I&cauthor_id=42155202)[ 4 ](https://pubmed.ncbi.nlm.nih.gov/42155202/#short-view-affiliation-4 "Department of Medicinal Chemistry, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt.. Electronic address: ismail_mohamed@pharm.suez.edu.eg."), [Khaled M Darwish](https://pubmed.ncbi.nlm.nih.gov/?term=Darwish+KM&cauthor_id=42155202)[ 5 ](https://pubmed.ncbi.nlm.nih.gov/42155202/#short-view-affiliation-5 "Department of Medicinal Chemistry, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt.; Department of Medicinal Chemistry, Faculty of Pharmacy, Galala University, New Galala 43713, Egypt. Electronic address: khaled.darwish@gu.edu.eg.") ### Affiliations * 1 Department of Medicinal Chemistry, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt.. Electronic address: nora.014170@pharm.suez.edu.eg. * 2 Department of Medicinal Chemistry, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt.. Electronic address: safaa_keshk@pharm.suez.edu.eg. * 3 Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt. Electronic address: ashraf.abadi@guc.edu.eg. * 4 Department of Medicinal Chemistry, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt.. Electronic address: ismail_mohamed@pharm.suez.edu.eg. * 5 Department of Medicinal Chemistry, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt.; Department of Medicinal Chemistry, Faculty of Pharmacy, Galala University, New Galala 43713, Egypt. Electronic address: khaled.darwish@gu.edu.eg. * PMID: **42155202** * DOI: [ 10.1016/j.bioorg.2026.109985 ](https://doi.org/10.1016/j.bioorg.2026.109985) Item in Clipboard Full text links Cite Display options Display options Format Abstract PubMed PMID ## Abstract Colorectal cancer (CRC) is the third most common cause of cancer-related mortality globally, claiming approximately 800,000 lives annually. Despite standard treatments like 5-fluorouracil, therapeutic success is frequently challenged by systemic toxicity, drug resistance, and high recurrence rates. This study aimed to overcome these limitations by developing novel thiazolyl-pyrazoline hybrids as dual inhibitors of the Adenosine 2 A Receptor (A2AR) and Epidermal Growth Factor Receptor (EGFR) that mechanistic convergence on the PI3K/AKT signaling axis regulating cell survival and apoptotic resistance. Using a molecular hybridization strategy based on lead pharmacophores Gefitinib and Tozadenant, three chemical series were developed and validated through a multi-disciplinary pipeline including molecular docking and iterated biological testing. Lead compounds, 6aii and 10b, have been identified as the most potent analogs of the series, exhibiting exceptional cytotoxicity against Caco2 cells at IC50 0.037 ± 0.10 μM and 0.6125 ± 0.13 μM, respectively. Mechanistic investigations confirmed these hybrids induce S and G2/M phase cell cycle arrest and stimulate restore apoptosis balance by upregulating pro-apoptotic genes (Caspase-3, TP53, and Bax) and downregulating the anti-apoptotic one (Bcl-2). Enzyme inhibition activity on EGFR and A2AR target depicted low-to-sub micromolar activity concentrations on respective targets (IC50 1.53 ± 0.12-8.37 ± 0.03 μM and 0.037 ± 0.21-0.6125 ± 0.15 μM, respectively). Compound 6ii further demonstrated the lowest cAMP expression biolevels confirming significant hampering of the A2AR's downstream signaling pathway. Moreover, the in vivo validation using AOM-induced CRC mouse models illustrated the effective restoration of the colonic crypt architecture, suppression of EGFR overexpression, and exhibition of favorable safety profiles regarding liver serum enzyme levels. This research provides a robust therapeutic framework for multi-target drug discovery in advanced colorectal cancer management. **Keywords:** A2AR; Colorectal cancer; Dual inhibition; EGFR; Thiazolyl-pyrazoline hybrids. Copyright © 2026 Elsevier Inc. All rights reserved. [PubMed Disclaimer](https://pubmed.ncbi.nlm.nih.gov/disclaimer/) ## Conflict of interest statement Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ## Similar articles * [ Design, synthesis and biological evaluation of a new series of thiazolyl-pyrazolines as dual EGFR and HER2 inhibitors. ](https://pubmed.ncbi.nlm.nih.gov/31493743/) Sever B, Altıntop MD, Radwan MO, Özdemir A, Otsuka M, Fujita M, Ciftci HI.Sever B, et al.Eur J Med Chem. 2019 Nov 15;182:111648. doi: 10.1016/j.ejmech.2019.111648. Epub 2019 Aug 28.Eur J Med Chem. 2019.PMID: 31493743 * [ Exploitation of novel pyrazolo[3,4-d]pyrimidine scaffold tethered to thiazole as potential EGFR/HER2 dual kinase inhibitor to overcome lapatinib resistant breast cancer: Design, synthesis, in silico docking and molecular dynamic simulation. ](https://pubmed.ncbi.nlm.nih.gov/40480106/) Salem IM, El-Sabbagh OI, Mostafa SM, Salama I, Al-Awadh MA, Alkhilaiwi FA, Yonbawi AR, Binothman N, Hayallah AM, Ibrahim TS.Salem IM, et al.Bioorg Chem. 2025 Aug;163:108671. doi: 10.1016/j.bioorg.2025.108671. Epub 2025 Jun 3.Bioorg Chem. 2025.PMID: 40480106 * [ Design, synthesis and biological evaluation of novel pyrazoline derivatives as dual EGFR/VEGFR-2 inhibitors for targeted cancer therapy. ](https://pubmed.ncbi.nlm.nih.gov/41075751/) Sawiris MM, Khalil OM, Halim PA, Hassan MSA.Sawiris MM, et al.Bioorg Chem. 2025 Oct;165:109075. doi: 10.1016/j.bioorg.2025.109075. Epub 2025 Oct 7.Bioorg Chem. 2025.PMID: 41075751 * [ Examining the 2-aryl-5-nitrobenzofuran-based hydrazones for anti-breast (MCF-7) cancer activity, potential to induce cell cycle arrest and inhibit receptor tyrosine kinases (VEGFR-2 & EGFR). ](https://pubmed.ncbi.nlm.nih.gov/40763666/) Nkoana JK, More GK, Elhenawy AA, Mphahlele MJ.Nkoana JK, et al.Eur J Med Chem. 2025 Nov 15;298:118018. doi: 10.1016/j.ejmech.2025.118018. Epub 2025 Aug 4.Eur J Med Chem. 2025.PMID: 40763666 * [ Rationally designed quinazolinone derivatives incorporating acetyl pyridine and thiazole scaffolds as dual EGFR/HER-2 anticancer agents: integrated biological evaluation, molecular profiling, and advanced computational studies. ](https://pubmed.ncbi.nlm.nih.gov/42217499/) El-Hema HS, El-Ghorab RA, Hawata MA, Nossier ES, Hussein MF, Elhendawy AT, Hamza MF, Abdel-Rahman AA.El-Hema HS, et al.Bioorg Chem. 2026 Sep 5;179:110052. doi: 10.1016/j.bioorg.2026.110052. Epub 2026 May 27.Bioorg Chem. 2026.PMID: 42217499 [ See all similar articles ](https://pubmed.ncbi.nlm.nih.gov/?linkname=pubmed_pubmed&from_uid=42155202) ## MeSH terms * Animals Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Animals%22%5BMeSH%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Animals) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42155202/) * Antineoplastic Agents* / chemical synthesis Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Antineoplastic+Agents%2Fchemical+synthesis%22%5BMAJR%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Antineoplastic+Agents) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42155202/) * Antineoplastic Agents* / chemistry Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Antineoplastic+Agents%2Fchemistry%22%5BMAJR%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Antineoplastic+Agents) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42155202/) * Antineoplastic Agents* / pharmacology Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Antineoplastic+Agents%2Fpharmacology%22%5BMAJR%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Antineoplastic+Agents) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42155202/) * Apoptosis / drug effects Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Apoptosis%2Fdrug+effects%22%5BMeSH%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Apoptosis) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42155202/) * Cell Proliferation / drug effects Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Cell+Proliferation%2Fdrug+effects%22%5BMeSH%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Cell+Proliferation) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42155202/) * Colorectal Neoplasms* / drug therapy Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Colorectal+Neoplasms%2Fdrug+therapy%22%5BMAJR%5D&sort=d
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