2. Academic Validation
  3. 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

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

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.

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