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Discovery of CA-4948, an Orally Bioavailable IRAK4 Inhibitor for Treatment of Hematologic Malignancies

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journal contribution
posted on 14.10.2020, 15:15 by Venkateshwar Rao Gummadi, Anima Boruah, Bharathi Raja Ainan, Brahma Reddy Vare, Srinivas Manda, Hari Prakash Gondle, Shiva Nagendra Kumar, Subhendu Mukherjee, Suraj T. Gore, Narasimha Rao Krishnamurthy, Sivapriya Marappan, Shilpa S. Nayak, Kavitha Nellore, Wesley Roy Balasubramanian, Archana Bhumireddy, Sanjeev Giri, Sreevalsam Gopinath, Dodheri S. Samiulla, Girish Daginakatte, Aravind Basavaraju, Shekar Chelur, Rajesh Eswarappa, Charamanna Belliappa, Hosahalli S. Subramanya, Robert N. Booher, Murali Ramachandra, Susanta Samajdar
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.