Discovery of 2-(4-Ureido-piperidin-1-yl)-4-morpholinothieno [3,2-D] Pyrimidines as Orally Bioavailable Phosphoinositide-3-Kinase Inhibitors with In Vitro and In Vivo Antitumor Efficacy in Triple-Negative Breast Cancer

  • J Med Chem. 2025 Oct 23;68(20):21282-21317. doi: 10.1021/acs.jmedchem.5c01164.
Shabber Mohammed  1  2 ,  Shabu Thakur  2  3 ,  Diksha Manhas  2  3 ,  Chilakala Nagarjuna Reddy  1  2  4 ,  Abhisheik Eedara  2  5 ,  Santosh K Guru  3 ,  Ajeet Singh  2  3 ,  Mahir Bhardwaj  2  3 ,  Vaishnavi Kambhampati  2  5 ,  Ramajayan Pandian  2  3 ,  Boobalan Gopu  2  3 ,  Shashi Bhushan  2  3  6 ,  Ram A Vishwakarma  1  2 ,  Sai Balaji Andugulapati  2  5 ,  Shashank K Singh  2  3 ,  Utpal Nandi  3  7 ,  Sandip B Bharate  1  2  4
Affiliations
  • 1. Natural Products & Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India.
  • 2. Academy of Scientific & Innovative Research (AcSIR), Ghaziabad 201002, India.
  • 3. Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India.
  • 4. Department of Natural Products & Medicinal Chemistry, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India.
  • 5. Applied Biology Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India.
  • 6. National Coordination Centre-Pharmacovigilance Programme of India (NCC-PvPI), Indian Pharmacopoeia Commission, Raj Nagar, Sector-23, Ghaziabad 201002, India.
  • 7. Bose Institute, Unified Academic Campus, Kolkata 700091, India.
PMID: 41047951 DOI: 10.1021/acs.jmedchem.5c01164
Abstract

The phosphoinositide-3-kinase-α is a key regulator of tumor progression across different cancers, including triple-negative breast Cancer. Herein, we explored thienopyrimidine and pyridofuropyrimidine cores to identify a PI3K-α inhibitor for the treatment of TNBC with favorable ADME properties. Structure-guided drug design and lead optimization efforts led to the identification of piperidine urea analog 50b as a PI3K-α inhibitor, which effectively inhibits the growth of MDA-MB-231 cells by targeting p110α, MAP kinase pathways, enhancing the expression of apoptotic proteins and impeding the cell's migratory capabilities. Compound 50b occupies the PI3K-α hinge pocket and forms H-bonding with VAL851, as well as with GLN859, a nonconserved residue linked to isoform selectivity. It exhibited a favorable ADME/PK profile, with 56% oral bioavailability, and demonstrated efficacy in the MDA-MB-231 xenograft model at peroral doses ranging from 25 to 75 mg/kg. Acute and repeated-dose toxicity studies confirmed an excellent safety profile, suggesting its potential for further development as a lead molecule for TNBC.

Products