Cancer is an increasingly severe health issue that affects individuals of all ages. In 2022, it was estimated that there were 1.9 million new cases of cancer diagnosed in the United States (US), with 609,360 of those cases resulting in cancer-related deaths. According to an analysis by the National Cancer Institute (NCI), by 2030, the number of individuals affected by cancer may reach 23.6 million, with an estimated 14 million of them succumbing to the disease. The development of cancer is often attributed to genetic abnormalities or mutations in proto-oncogenes or tumour suppressor genes, which are inherited conditions [1], [2]. Proto-oncogenes are genes that play a vital role in regulating cell cycle progression. However, when these genes undergo mutations, they can transform into oncogenes, which promote uncontrolled growth in normal cells and lead to the formation of cancerous tissue [3].

Despite significant advancements in cancer treatment, numerous limitations persist. These include the ability of drugs to specifically target certain types of cancer cells, the occurrence of side effects, and the capacity of cancer cells to develop multidrug resistance and become unresponsive to conventional therapies [4]. Consequently, the development of novel small molecules that possess both potency and selectivity remain a challenging endeavour for medicinal chemists [5], [6].

According to data from the World Health Organization (WHO), breast and liver cells among the leading causes of mortality [7]. Moreover, developing nations have a significant burden, with approximately 50 % of breast cancer cases and 58 % of related deaths occurring in these regions [8]. Furthermore, liver cancer exhibits a high incidence rate, with approximately 83 % of cases detected in Asia and neighbouring communities [9]. Due to the nature of current cytotoxic chemotherapies and the resulting resistance, they are associated with significant side effects [10]. As a result, there is a constant need to explore new, improved, and safer anticancer agents that exhibit enhanced selectivity toward cancer cells [11], [12]. Modern research approaches aim to target specific critical aspects of cancer cells, such as disordered, mutated, or overexpressed proteins. Among these, protein kinases have emerged as attractive biological targets for the development of novel anticancer treatments, leading to extensive clinical use and investigation of various kinase inhibitors [13].

Cyclin-dependent kinases (CDKs) are a group of important enzymes that maintain a delicate balance of activity and inactivity to ensure the progression of the eukaryotic cell cycle through its different phases. Protein kinases, a diverse family of enzymes, catalyse the transfer of a phosphate group from adenosine triphosphate to specific serine (Ser) and threonine (Thr) residues, playing a crucial role in cell proliferation [14], [15]. A critical component of the cell cycle is cyclin-dependent kinase 2 (CDK2), which plays a crucial role in directing the G1/S cell cycle transition phase and regulating the G2/M transition phase [16], [17], [18], [19]. CDKs are essential for governing key physiological functions such as gene transcription, cell cycle progression, and cell proliferation [20]. In human malignancies, including ovarian, breast, uterine, lung, and thyroid carcinomas, osteosarcoma, and melanoma, CDK2 is primarily associated with regulatory elements, such as overexpressed Cyclin A or E [21].

Mammalian cells contain 20 members of the CDKs family, denoted as CDK 1–20, which are activated by binding with their corresponding cyclin counterparts, transcription factor components [21]. Cyclins, encoded by the human genome, serve as regulatory subunits, and facilitate the activation of CDKs substrates [22], [23], [24], [25], [26]. The CDK, numbering, possess a conserved Adenosine triphosphate (ATP) binding site and a cyclin-binding domain resembling PSTARIRE, as well as an activating T-loop [27]. Specific cyclin regulatory subunits, such as cyclins A, B, C, D, and E, interact with CDKs to modulate their activity. While CDKs 1, 2, 3, 4, and 10 function at different stages of the cell division process, CDKs 7, 8, and 9 are involved in gene transcription through the regulation of Ribonucleic Acid (RNA) polymerase II. The transcription levels of each CDK vary significantly across different phases of the cell cycle. In mammals, the CDK1 complexed with cyclin A/B controls the transition from G2 to M−phase. CDK4 and CDK6, along with cyclin D, regulate progression from G1 to S-phase, stimulating Deoxyribonucleic Acid (DNA) synthesis. Additionally, CDK2 complexed with cyclin E/A facilitates the completion of Deoxyribonucleic Acid (DNA) synthesis in the S-phase. CDK7, CDK8, and CDK9, in complex with cyclins H, C, and T respectively, exert control over fundamental transcriptional events [22], [28]. Notably, the retinoblastoma protein is generated when CDK2, an important member of the CDKs family, binds to cyclin E. This mechanism, involving the collaboration between cyclin E and CDKs, promotes the activation of transcription. Phosphorylation of factor E2F and retinoblastoma protein (pRb) facilitates the cell cycle transition from G1 to S phase [29]. Similarly, when CDKs are complexed with E2F, they enable continuous Deoxyribonucleic Acid (DNA) replication while ensuring timely E2F deactivation. Consequently, CDK2 has emerged as a crucial therapeutic target for cancer treatment [22], making it a potential candidate for modern, promising therapies against various cancers [30]. Several CDK inhibitors have been developed for use in anticancer medications. However, first-generation drugs like UCN-01, Flavopiridol, Olomoucine, and R-roscovitine (Fig. 1) have shown limited efficacy or significant toxicity in clinical investigations [20], [31], [32]. Alternatively, the CDK2 inhibitor purine analogue R-roscovitine (III) demonstrated antitumor efficacy against MCF-7 and HepG2 cancer cells, with IC50 values of 7.8 and 25.9 µM, respectively [33]. Furthermore, second-generation CDK inhibitors can be categorized as follows: (1) Substances exhibiting various CDKs activities, such as SNS-032 (v) and R547 (vi) [33], [34], [35], [36], [37], [38] (2) Substances like AT-7519 (vii; CDK2) and P276-00 (viii; CDK4/CDK6), selectively inhibiting CDK4/CDK6 or CDK2, (Cyclin-dependent kinases) respectively. (3) Drugs that enhance their anticancer efficacy by targeting CDKs while also affecting off-kinase targets. Members of this class include ZK-304709 (ix; CDK/VEGFR activity) and JNJ-7706621 (x; CDK/Aurora A and B activity) (Fig. 1) [39], [40], [41].

In 2015, compound vii was recognized by the Food and Drug Administration (FDA) for the treatment of breast carcinoma. Several research studies have supported the targeting of CDK2 as a strategy to slow the spread of cancer [42]. Recently, several Cyclin-dependent kinases 2 CDK-20 inhibitors, including roscovitine with a 2-aminopurine scaffold [43], [44], [45], [46], have been discovered and are now being investigated in clinical trials for the treatment of various types of tumours. The presence of the aminopyrimidine moiety in compounds 1–8 is significant as it is found in many reported CDK2 inhibitors [47], [48], [49], [50], [51], [52], [53], [54], [55], [56] (Fig. 2). The 2-amino benzothiazole structure, as demonstrated by compounds 6 and 8 [55], [57], is also highly significant in pharmaceutical chemistry and is commonly found in bioactive compounds, particularly those targeting cancer. Additionally, the triazole nucleus offers a wide range of applications in the development of novel anticancer compounds [58], [59], [60]. S-benzo[4,5] thiazolo[2,3-c]triazole (vii) has shown high cytotoxicity against the A549 and MCF-7 cell lines in a study by Abdelazeem et al. [57], with an IC50 value of 4.29 M. This effect was attributed to the strong inhibition of CDK-2/cyclin A. Structural studies of earlier compounds revealed that most inhibitors possess a similar amino-substituted nitrogenous heterocyclic core, which likely contributes to increased selectivity within the Adenosine triphosphate (ATP) pocket of CDK2. Clinical studies have been initiated for several small molecule inhibitors of CDK2 (Fig. 3). Many of these inhibitors interact with important components through the pyrimidine and pyrazole groups in their backbones. Pyrimidine and pyrazole analogues belong to a significant family of bioactive compounds with diverse medicinal applications. They exhibit a wide range of pharmacological effects, including anti-cancer, anti-viral, anti-HIV, anti-hypertensive, anti-tuberculous, diuretic, anti-bacterial, anti-fungal, and anti-epileptic activities. Furthermore, there are various classes of chemotherapy drugs based on clinical studies [61] (Fig. 4, Fig. 5).

This study highlights recent advances in effective CDK2 inhibitors in the field of bio-organic chemistry. It presents numerous heterocyclic and aromatic scaffolds for CDK2 inhibitors along with their various biological actions. The topic of structure–activity relationship (SAR) is also discussed, with appropriate examples provided.