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Discovery of CA-4948, an orally bioavailable IRAK4 inhibitor for treatment of hematologic malignancies

DOI: 10.1021/acsmedchemlett.0c00255 DOI Help

Authors: Venkateshwar Rao Gummadi (Aurigene Discovery Technologies Ltd) , Anima Boruah (Aurigene Discovery Technologies Ltd) , Bharathi Raja Ainan (Aurigene Discovery Technologies Ltd) , Brahma Reddy Vare (Aurigene Discovery Technologies Ltd) , Srinivas Manda (Aurigene Discovery Technologies Ltd) , Hari Prakash Gondle (Aurigene Discovery Technologies Ltd) , Shiva Nagendra Kumar (Aurigene Discovery Technologies Ltd) , Subhendu Mukherjee (Aurigene Discovery Technologies Ltd) , Suraj T. Gore (Aurigene Discovery Technologies Ltd) , Narasimha Rao Krishnamurthy (Aurigene Discovery Technologies Ltd) , Sivapriya Marappan (Aurigene Discovery Technologies Ltd) , Shilpa S. Nayak (Aurigene Discovery Technologies Ltd) , Kavitha Nellore (Aurigene Discovery Technologies Ltd) , Wesley Roy Balasubramanian (Aurigene Discovery Technologies Ltd) , Archana Bhumireddy (Aurigene Discovery Technologies Ltd) , Sanjeev Giri (Aurigene Discovery Technologies Ltd) , Sreevalsam Gopinath (Aurigene Discovery Technologies Ltd) , Dodheri S. Samiulla (Aurigene Discovery Technologies Ltd) , Girish Daginakatte (Aurigene Discovery Technologies Ltd) , Aravind Basavaraju (Aurigene Discovery Technologies Ltd) , Shekar Chelur (Aurigene Discovery Technologies Ltd) , Rajesh Eswarappa (Aurigene Discovery Technologies Ltd) , Charamanna Belliappa (Aurigene Discovery Technologies Ltd) , Hosahalli S. Subramanya (Aurigene Discovery Technologies Ltd) , Robert N. Booher (Curis Inc) , Murali Ramachandra (Aurigene Discovery Technologies Ltd) , Susanta Samajdar (Aurigene Discovery Technologies Ltd)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Acs Medicinal Chemistry Letters

State: Published (Approved)
Published: October 2020

Abstract: Small molecule potent IRAK4 inhibitors from a novel bicyclic heterocycle class were designed and synthesized based on hits identified from Aurigene’s compound library. The advanced lead compound, CA-4948, demonstrated good cellular activity in ABC DLBCL and AML cell lines. Inhibition of TLR signaling leading to decreased IL-6 levels was also observed in whole blood assays. CA-4948 demonstrated moderate to high selectivity in a panel of 329 kinases as well as exhibited desirable ADME and PK profiles including good oral bioavailability in mice, rat, and dog and showed >90% tumor growth inhibition in relevant tumor models with excellent correlation with in vivo PD modulation. CA-4948 was well tolerated in toxicity studies in both mouse and dog at efficacious exposure. The overall profile of CA-4948 prompted us to select it as a clinical candidate for evaluation in patients with relapsed or refractory hematologic malignancies including non-Hodgkin lymphoma and acute myeloid leukemia.

Journal Keywords: IRAK4; bicyclic heterocycles; SAR; CA-4948; AML; DLBCL

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 25/11/2020 08:38

Discipline Tags:

Drug Delivery Non-Communicable Diseases Health & Wellbeing Cancer Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)