2. Academic Validation
  3. Synthesis of β-boswellic acid-amino acid conjugates for targeting KRASG13D mutant colon cancer

Synthesis of β-boswellic acid-amino acid conjugates for targeting KRASG13D mutant colon cancer

  • Eur J Med Chem. 2026 Jan 15;302(Pt 2):118336. doi: 10.1016/j.ejmech.2025.118336.
Arem Qayum 1,  Simmi Sharma 2,  Syed Mohmad Shah 3,  Sourav Kumar 4,  Mohamad Sakib Abdullah 5,  Mubashir Javed Mintoo 1,  Anjna Sharma 6,  Utpal Nandi 2,  Naiem Ahmed Wani 4,  Rajkishor Rai 4,  Shashank Kumar Singh 7,  Bhahwal Ali Shah 8
Affiliations

Affiliations

  • 1 Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, 180001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
  • 2 PK-PD, Toxicology and Formulation Division, CSIR-Indian Institute of Integrative Medicine, Jammu, 180001, India.
  • 3 Sher-e-Kashmir University of Agricultural Sciences & Technology of Kashmir, Srinagar, 190001, India.
  • 4 Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India; Natural Products and Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Jammu, 180001, India.
  • 5 Natural Products and Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Jammu, 180001, India.
  • 6 PK-PD, Toxicology and Formulation Division, CSIR-Indian Institute of Integrative Medicine, Jammu, 180001, India; Chitkara University School of Pharmacy, Chitkara University, Himachal Pradesh, 174103, India.
  • 7 Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, 180001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India. Electronic address: sksingh.iiim@csir.res.in.
  • 8 Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India; Natural Products and Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Jammu, 180001, India. Electronic address: bashah.iiim@csir.res.in.
PMID: 41232293 DOI: 10.1016/j.ejmech.2025.118336
Abstract

The synthesis and cytotoxicity evaluation of a series of β-boswellic acid-amino acid conjugates have been described to enhance anti-cancer efficacy, with a focus on KRASG13D-mutant colorectal Cancer (CRC) cells. Among these, compound 8b, which incorporates a hydrophilic urea linker, demonstrated significantly improved aqueous solubility, cellular uptake, and cytotoxicity. In vitro, 8b showed potent activity with IC50 values of 1.95 ± 0.71 μM (HCT-116G13D) and 2.16 ± 1.06 μM (HCT-15G13D), compared with β-boswellic acid (IC50 > 25 μM). Compound 8b induced G1-phase arrest, oncogene-induced senescence, and mitochondrial membrane depolarization in both cell lines. Mechanistic studies revealed selective inhibition of CDK6 (IC50 = 703 nM) and downregulation of TWIST1, key mediators of tumor progression and drug resistance. Molecular docking and MD simulations confirmed strong and stable interactions with CDK6 and KRASG13D proteins. In vivo, 8b exhibited significant tumor growth inhibition in multiple murine models (up to 89.58 % TGI in EAC) with minimal systemic toxicity and favorable pharmacokinetic parameters.

Keywords

CDK6; Colon cancer; KRAS(G13D); Senescence; TWIST1; β-Boswellic acid.

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