CHARACTERIZATION AND DEVELOPMENT OF CHEMICAL COMPOUNDS TARGETING LUNG, PANCREATIC, AND COLORECTAL CANCERS: A COMPREHENSIVE REVIEW
Neelam Hazoor Zaidi
Department of Basic Science, Umanand Prasad School of Medicine and Health Science, The University of Fiji, Saweni campus, Lautoka, Fiji.
Abstract
Due to high incidence, aggressive progression, and limited therapeutic efficacy, lung, pancreatic, and colorectal cancer represent a significant share of cancer-related deaths. Cancer remains a major cause of global morbidity and mortality. Despite considerable progress in traditional treatments such as surgery, chemotherapy, radiotherapy, targeted therapy, and immunotherapy, challenges like drug resistance, systemic toxicity, tumor heterogeneity, and recurrence continue to hinder long-term success. Therefore, the identification, study, and creation of new chemical compounds have become a promising approach to improving cancer treatment outcomes. By integrating current knowledge on chemical compound development and mechanistic insights across these three major cancer types, this review identifies existing research gaps, summarizes recent therapeutic advances, and outlines future directions for the rational design of safer and more effective anticancer agents. The findings presented herein are expected to support researchers and clinicians in advancing precision oncology and developing next-generation therapeutics for improved patient outcomes. With cancer being the rising cause of morbidity and mortality in the world today challenges the global health systems. Cancer is often diagnosed at advanced stages and possesses poor prognosis due to cancer having high metastatic potential and limited response to treatment therapies. The process of oncology despite extensive advancement such as chemotherapy regimens faces issues of drug resistance, systemic toxicity and lack of ability to detect tumor specificity. This review provides a comprehensive overview of recent advances in the development of chemical compounds targeting lung, pancreatic, and colorectal cancers. It discusses the structural diversity, biological activities, and molecular mechanisms of natural products, synthetic molecules, and semi synthetic derivatives with demonstrated anticancer potential. Particular emphasis is placed on their interactions with key signaling pathways involved in tumor initiation and progression.
Keywords: Cancer, drug development, molecular targets, natural products, synthetic compounds, targeted therapy.
INTRODUCTION
Cancer is referred to as a group of diseases characterised by abnormal development of cells that divides uncontrollably and can infiltrate and destroy normal cells, thus this research will specifically focus on lung, pancreatic and colon cancer. It often has the ability to spread throughout the body ranking it the 2nd leading cause of death worldwide (Mayo Clinic , 2022). There are many other type of cancers including breast cancers that are common in females and prostate cancer in males followed by lung and skin cancer affecting the population as a whole. It is necessary that cancers are detected early in order to treat the cancer effectively and minimize damage to normal cells however due to late detections there is increased morbidity and mortality(World Health Organization, 2025).
To initiate with, lung cancer is caused by harmful cell growth in lungs. Lung cancer starts usually in the lung airways( bronchi or bronchioles) or small air sacs (alveoli) then it moves to the lungs referred to as metastatic lung cancer. There are two types of lung cancer: non-small cell lung cancer and small cell lung cancer. A person with lung cancer will experience cough, bone pain, jaundice, shortness of breath and wheezing(Mayo Clinic, 2024a). However there are other types of lung cancers which are lymphomas, sarcomas and pleural mesothelioma. Lung cancers have various stages that tend to worsen with time(Clinic, 2022). As of 2020 there were 2.21 million new cases of lung cancers followed by 1.8 million deaths recorded globally (World Health Organization, 2025) making lung cancer the leading cause of death worldwide.
Moreover, pancreatic cancer is a type of cancer that begins growth as a growth of cells in the pancreas which lies behind the lower part of the stomach. The most common type of cancer affecting pancreas is pancreatic ductal adenocarcinoma which is rarely detectable at early stage making it life threatening. A person with pancreatic cancer will lose appetite, have dark -colored urine, itching, and belly pain radiating to sides and back(Mayo Clinic, 2024). Pancreatic cancer as of 2023 has showcased a rise in young females than men due to poor lifestyle and addiction to alcohol use and chronic smokers(Cedars Sinai, 2023) which hikes the death toll as of 2020 to 466,000 deaths worldwide(Sung et al., 2021).
Furthermore, descending the human body the common type of cancer affecting the population is colon cancer. Colon is the last part of the digestive tract and it is the first and longest part of the large intestine. The cancer cells initiate from the lining of the intestine growing into small clumps as polyps and enlarged into cancerous cells. Colon cancer is not easily detected at early stage however a person with blood in stool( hematochezia), is a sign of having colon cancer(Mayo Clinic, 2023). Colon cancer is followed by lung cancer having a peak death toll of 935,000 deaths since 2020(Sung et al., 2021).
However, with advancing scientific knowledge with the help of small molecule chemical compounds there has been introduction of alternative chemicals to treat cancers. These compounds having characteristics of favorable pharmacokinetics, oral bioavailability, and ability to penetrate solid tumors makes it suitable for targeting and overcoming intracellular pathways and resistance, thus it allows not only extracellular targets but also intracellular where chemical compounds can control the influence of oncogenic drivers(Open Access Government, n.d.).
Conclusively, this research project will target to characterise biological and medical chemistry and pharmacological profiling of small molecular chemical compounds that are used as alternatives for treatment over chemotherapy and surgery as small molecular compounds have high specificity of penetration in cells that targets lung, pancreatic,and colon cancer.
Cancer
Cancer is a disease where there is abnormal and uncontrolled growth of cells. It initiates with small growth that starts to spread called metastatic cancer. The abnormal cells start to divide rapidly and invade nearby tissues and if in case infects blood then multiple organs are under stress. There are two main categories of cancer: hematologic( blood cancers) and solid tumors. Common cancers are lung, breast, colorectal and prostate cancers that affect the global population making them the primary cause of deaths.
Lung cancer
Lung cancer, also called lung carcinoma, is a malignant tumor originating in the lungs. It occurs due to genetic damage to the DNA in airway cells, often caused by cigarette smoking or exposure to harmful chemicals. These damaged cells multiply uncontrollably, leading to tumor formation. If untreated, the tumors spread throughout the lung, impairing its function. Eventually, lung tumors metastasize, spreading to other parts of the body.(Mayo Clinic, 2024a).
Lung cancer is the most common cancer worldwide, representing 12.3% of all cases, with an estimated 2.2 million new cases and 1.8 million deaths projected in 2025. Tobacco smoking is the primary cause, responsible for 80%–90% of lung cancers in smokers. Incidence varies significantly by geography, race, and gender, with some studies indicating that women may be more susceptible to lung cancer from tobacco carcinogens. A lifetime smoker has a 20- to 30-fold higher risk of developing lung cancer compared to a nonsmoker. In 2000, lung cancer caused approximately 1.1 million deaths worldwide, accounting for 17.8% of all cancer deaths. However, only 11% of heavy smokers develop lung cancer, suggesting a potential role of genetic factors in susceptibility. Nicotine addiction is the powerful engine that prevents smokers from quitting. The many lung cancer-specific carcinogens (including polycyclic aromatic hydrocarbons and nitrosamines) in the particulate matter of tobacco smoke have to be metabolized before they are either secreted or can bind to DNA with the formation of adducts. DNA adducts may be repaired or lead to apoptosis. If they persist, miscoding mutations in key genes such as P53 or RAS may cause genetic instability, leading to further mutational damage and eventually to cancer. ( John D Minna et al).
Classification
Lung cancer is primarily classified into two main types based on the size and appearance of malignant cells as observed by a histopathologist under a microscope:
Symptoms
(Mayo Clinic, 2024a).
II: Pancreatic cancer
Pancreas is a vital organ that is located in the abdomen region which is on the left side behind the stomach. It plays a crucial role in the digestion process by producing digestive juices that aids in digestion of food and it releases hormones such as insulin to break down glucose regulating sugar levels.
A cancer in pancreas is when pancreatic cells mutate( change) and uncontrollably divide forming a tumor. Pancreatic cancer is not detectable at early stage until it metastases which makes it resistant to common cancer drugs(Cleveland clinic, 2023). Initiation of the growth of tumor cells in pancreas grows in the ducts of pancreas known as adenocarcinoma tumors that surround the pancreatic duct. Growth of tumor cells leads to variation and mutation in DNA which results in abnormal cell growth and multiplication.
The global standing of pancreatic cancer as of 2022 under World Cancer Research Fund is 12th most common cancer with 510,992 cases worldwide(World Cancer Research Fund, 2024). Mainly pancreas cancer is most common in individuals with smoking habits, type 2 diabetes, chronic inflammation of pancreas, family history, obese people and those with chronic alcohol consumption(Mayo Clinic, 2024b).
III: Colon cancer
Colon is the first and longest part of the large intestine which is part of the digestive system as it is a long tube that helps carry digested food to your rectum and out of your body. It is an important part of the digestive system that breaks down food for body use.
A cancer cell starts to develop in the colon lining is known as colon cancer or colorectal cancer. Just like other cells in the human body cells in the colon undergo continuous growing, dividing and dying in healthy individuals, however in colon cancer the cells present in the lining of the colon and rectum area continuously grow without dying out even though they are supposed to die out to allow new cell growth. This continuous cell growth without cell death leads to uncontrolled cell growth that eventually grows into small polys. Once there is growth of polys it is not yet a cancerous cell but with time as it grows large in size it becomes cancerous tumors. An individual with colorectal cancer at first doesn’t have symptoms thus making it hard to detect at an early stage. Colorectal cancer is often diagnosed at advanced stages where treatment options are limited and chances of survival are diminished.
According to the World Health Organization it is noted that colorectal cancer is the 3rd most common cancer worldwide that accounts for 10% of all cancer cases and the 2nd leading cause of death worldwide. It was also noted that colon cancer mainly affects older individuals with many cases with people aged 50 years and above. People with a history of inflammatory bowel disease, family history of colon cancers,diabetic, obese, smokers, alcohol intakers, and any previous radiation therapy of cancers and older age individuals are most susceptible to colon cancer.
Symptoms of pancreatic cancer
dull and persistent pain, radiating sometimes
Stages :
Small Chemical compounds Targeting Cancer
With growing drawbacks from current treatment options such as immunotherapy and chemotherapy there is a drastic need for new treatments for colon cancer that targets the oncogenic drivers of colon cancers. Studies show that by targeting site Cdc42 with small molecular drug like AZA197, helps suppress primary colon cancer initiation and ensures survival of individuals by regulation of PAK1 in preclinical xenograft( graft tissue taken from one species and grafted into another species).
A small signalling protein, the Rho GTPases plays a crucial role in regulating cellular processes that includes, cytoskeleton organization, cell polarity, transcriptional dynamics cell cycle, cell motility, vesicle trafficking and regulation of tumor progression( promotes cancer cell proliferation, migration and invasion). It is a protein that inhibits or acts as a molecule switch, where it switches active GTP-bound state into inactive GDP-bound state(Liu et al., 2024).
A: TARGETING Cdc42 cells
Cancer poses a threat to health and longevity of life as cancer has characteristics such as sustaining proliferative signals, evading growth suppressors, and resisting cell death. Thus, Rho GTPases expression levels in cancer are altered(Liu et al., 2024). Rho GTPases control numerous signalling pathways that help regulate gene expressions, cell migration, cell proliferation and cell survival that are all part of all stages of cancer progression.
Therefore, AZA197 inhibits selectively Cdc42 that is used for treatment of colon cancer which was designed from information obtained from drugs that inhibit Rho GTPases activity that leads to inhibition of cell growth, motility, and survival pathways making therapeutic agents for cancer cells. This was investigated using the mouse xenograft method that resembled human colon cancer cells, thus tumors were removed after the above treatment(Zins et al., 2013). AZA197 selectively inhibits Cdc42 which is a member of Rho GTPase; it does not inhibit Rac1 or RhoA ( indicates high target specificity).
AZA197 helps:
AZA197 impairs Cdc42-mediated cell motility and invasion in colon cancer cells by disrupting actin cytoskeleton reorganization and filopodia formation, confirming its anti-metastatic potential(Zins et al., 2013). JAK2 and STAT3 signaling pathways are activated by interleukin-6, which regulates cell growth, differentiation, immune response and it is abnormally activated in individuals with cancers. It is a viable target for colon cancer therapy, Ergotamine is an FDA-approved drug that demonstrates significant anti-cancer potential and could be repurposed for colon cancer treatment(Chandrasekhar et al., 2024).
JAK2 pathway inhibition induces cell cycle arrest and apoptosis in colon cancer. Some JAK2 inhibitors include ruxolitinib, baricitinib and fedratinib that target JAK1 AND JAK2(Chandrasekhar et al., 2024).
C: Enhancing chemoresistance with combined kras and TP53
Individuals with colon cancer often have resistance to chemotherapy due to genomic variation where APC, TP53, KRAS, and PIK3CA are the genes that are mutated in advanced colon cancer patients. With the help of CT scan and carcinoembryonic antigen levels the mutated genes in colon cancer and its sensitivity to chemotherapy drugs were assessed.
Chemotherapy is used for patients with stage III or stage IV cancer where often the anticancer drugs in patients with metastatic cancer finally succumb to chemoresistance as the tumors become drug resistant and makes it the reason behind treatment failures and deaths in colon cancer patients(Marbun, Erlina and Lalisang, 2022).
Having identified the mutation of genes allows understanding the treatment option better.
Genes:
D: Targeting SMAD4
SMAD4 is a crucial mediator in the Transforming Growth Factor Beta (TGF-β) signaling pathway, governing essential cellular processes like cell growth, differentiation, apoptosis and migration . In this pathway, TGF-β binding to cell surface receptors triggers the activation of SMAD proteins, forming a complex with SMAD4.
Induces cell cycle arrest controls cell proliferation and eliminating damaged cells, helps in wound healing and control metastasis E. TARGETING MET
MET has been considered as a promising drug target for the treatment of MET-dependent diseases, particularly non-small cell lung cancer (NSCLC). Small molecule MET inhibitors with mainly three types of binding modes (Ia/Ib, II, and III) have been developed (Chaofan Wang, Xiaoyun Lu, 2023)
Small chemical compounds for targeting lung cancer
Lung cancer is traditionally classified into non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), and carcinoid. NSCLC accounts for approximately 80% of all lung cancers and is further sub typed into adenocarcinoma, squamous cell carcinoma, and large cell carcinoma . In addition to EGFR, ALK, KRAS, MET, AND TP53, there are several other molecular abnormalities that could potentially be treated with drugs already approved for other malignancies or with investigational agents (Sacha I Rothschild, 2015).
For targeting EGFR
Epidermal growth factor receptors (EGFRs), also known as ErbB1 and HER1, are part of the receptor tyrosine kinase family. Inhibiting EGFR's tyrosine kinase activity is a promising approach for cancer therapy. Various small-molecule EGFR tyrosine kinase inhibitors (EGFR-TKIs), from medicinally privileged compounds to commercial drugs, have been reviewed with emphasis on their molecular structure and mechanisms of action.
Because the EGFR signaling pathway regulates cell proliferation, growth, survival, and differentiation, and mutated EGFR genes cause overproduction of EGFR protein leading to several cancers, understanding the molecular interactions between EGFR and its inhibitors is crucial. This will enable the development of more effective and selective EGFR-TKIs, improving cancer treatment and saving more lives.
Fourth-Generation EGFR-TKIs: EAI001, EAI045, DDC4002, DDC-01-163- Small molecule chemical compounds are more effective means of treating cancers as small molecules are easily able to enter cells and reach both the extracellular and intracellular genes. It helps to easily modulate specific proteins that help cancer cells to grow and survive.
Most importantly it helps bypass resistance mechanisms that reduce systemic toxicity as the small molecules are target specific with high precision and availability of the inhibitor drugs in pills that improves patient compliance. These chemicals can also be used with chemotherapy, radiation and immunotherapy as it helps improve immune response and reduces metastasis.Zaidi et al. (2011) demonstrated the synthesis, surface functionalization, and bioconjugation of ligand-passivated quantum dots for sensitive biological detection, highlighting their potential as versatile nanoplatforms for biomarker detection and targeted cancer diagnostics.
CONCLUSION
Continuous advancements in chemical biology have led to the discovery and development of novel anticancer compounds with enhanced specificity and efficacy. The combination of chemical synthesis, computational drug design, and biological evaluation is vital for identifying innovative therapeutic approaches against cancer. Interdisciplinary collaborations have played a significant role in this rapidly advancing field, resulting in groundbreaking discoveries in targeted therapies, small-molecule inhibitors, and promising compounds with unique mechanisms of action(Dr. Mateusz Kciuk and Dr. Beata Marciniak, 2025). This research project focused more on the small molecule inhibitors and targeted therapies. Colorectal cancer cells grow and divide without dying leading to development of tumor. According to the World Health Organization it is noted that colorectal cancer is the 3rd most common cancer worldwide. APC, KRAS, TP53, PIK3CA, and MSI are the most commonly mutated genes in colon cancer. Several small molecule inhibitors are discussed above for targeting these mutated genes. A cancer in pancreas is when pancreatic cells mutate( change) and uncontrollably divide forming a tumor. The global standing of pancreatic cancer as of 2022 under World Cancer Research Fund is 12th most common cancer with 510,992 cases worldwide. Along with surgery there are several therapies used to treat pancreatic cancer such as ; radiotherapy and chemotherapy. KRAS, p16/CDKN2A, TP53 and SMAD4/DPC4 are the commonly mutated genes in pancreatic cancer. Several methods of inhibition for the mutated genes are discussed above. Lastly , lung carcinoma is a malignant tumor that stars in the lungs and eventually metastasizes to other parts if not treated. The most common cause of lung cancer is cigarette smoking. Lung cancer is the most common form of cancer in the world (12.3% of all cancers), with an estimated 1.2 million new cases in 2000 . EGFR, ALK, KRAS, MET, and TP53 are the commonly mutated genes in lung cancer.
ACKNOWLEDGEMENT
Author is thankful fo the The University of Fiji, Saweni campus, Lautoka, Fiji to provide necessary facilities for this work.
AUTHOR’S CONTRIBUTIONS
Zaidi NH: conceptualization, literature survey, writing original draft. Final manuscript was checked and approved by all authors.
DATA AVAILABILITY
The associated author can provide the empirical data used to support the study's conclusions upon request.
CONFLICT OF INTEREST
There are no conflicts of interest in regard to this project.
REFERENCES