Abstract Around 95% of pancreatic tumors harbor mutations in codons G12, G13, and Q61 of the KRAS gene. Thus, there is a significant unmet need for the development of selective KRAS inhibitors. Alternatively, the four-membered cyclic amides, commonly known as β-lactams, are found in nature. Since their discovery, beta-lactam antibiotics have played a central role in fighting against bacterial infections. However, the ‘upgradation’ of β-lactams from one generation to another is required for drug resistance, which is predominantly due to bacterially produced β-lactamase enzymes that hydrolyze the highly strained β-lactam ring because of tremendous angular strain. We hypothesize that, as cancer cells do not produce β-lactamase enzymes, the β-lactam ring’s stability should be higher in tumor environments. With appropriate chemical modifications, β-lactams should inhibit proteins responsible for the proliferation, angiogenesis, and metastasis of various cancers, including hepatobiliary-pancreatic carcinomas (HPCs). HPCs include hepatocellular carcinoma (HCC), biliary tract cancers (BTCs), and pancreatic cancer (PanCa), which are highly challenging to treat and manage. As a part of our ongoing research in developing small molecule inhibitors from natural sources through chemical modifications (semi-synthetic) and/or by appropriate structure-based design and synthesis of structural mimics of natural products, we have successfully carried out computer-assisted design, multi-step synthesis, and in vitro anti-pancreatic cancer evaluation of a small series of β-lactams as KRAS inhibitors. There are a few methods for synthesizing the beta-lactam core unit, and we used the 2+2 ketene-imine cycloaddition (Staudinger) reaction followed by derivatization to synthesize the target 2-azetidinones. Further, MTT and apoptosis assays, cell cycle analysis, gamma-H2AX (phospho-Ser139) staining, and BrdU incorporation studies were conducted. Most of the products in this series demonstrated excellent (in vitro) activity in pancreatic cancer cell lines. The newly synthesized β-lactams demonstrated hundreds- to thousands-fold higher activity than the positive control, gemcitabine, in PANC-1 cells. Comparison of IC50 values in pancreatic cancer cells (PANC-1) and normal pancreatic epithelial cells (NPC) shows that almost all compounds exhibit 3-359 times greater selectivity for PANC-1 than for NPC. The in silico, and in vitro validated β-lactams could successfully serve as an entry point for clinical trials after appropriate in vivo evaluation. The work will significantly strengthen the fight against pancreatic cancer and undoubtedly foster a collaborative environment for future research. Citation Format: Debasish Bandyopadhyay, Tushar Debnath, Attrayo Mukherjee, Jonathan Rock, Omar Espino, Vivek Kumar Kashyap, Subhash C. Chauhan. Beta-lactams, structural mimics of natural products, as anti-pancreatic cancer agents: A pilot study abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3670.
Bandyopadhyay et al. (Fri,) studied this question.