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

  • ACS Med Chem Lett. 2020 Oct 14;11(12):2374-2381. doi: 10.1021/acsmedchemlett.0c00255.
Venkateshwar Rao Gummadi  1 ,  Anima Boruah  2 ,  Bharathi Raja Ainan  1 ,  Brahma Reddy Vare  1 ,  Srinivas Manda  1 ,  Hari Prakash Gondle  1 ,  Shiva Nagendra Kumar  1 ,  Subhendu Mukherjee  1 ,  Suraj T Gore  1 ,  Narasimha Rao Krishnamurthy  1 ,  Sivapriya Marappan  1 ,  Shilpa S Nayak  1 ,  Kavitha Nellore  1 ,  Wesley Roy Balasubramanian  1 ,  Archana Bhumireddy  1 ,  Sanjeev Giri  1 ,  Sreevalsam Gopinath  1 ,  Dodheri S Samiulla  1 ,  Girish Daginakatte  1 ,  Aravind Basavaraju  1 ,  Shekar Chelur  1 ,  Rajesh Eswarappa  2 ,  Charamanna Belliappa  1 ,  Hosahalli S Subramanya  1 ,  Robert N Booher  3 ,  Murali Ramachandra  1 ,  Susanta Samajdar  1
Affiliations
  • 1. Aurigene Discovery Technologies Ltd., 39-40 KIADB Industrial Area, Electronic City Phase II, Bangalore 560 100, India.
  • 2. Aurigene Discovery Technologies Ltd., Bollaram Road, Miyapur, Hyderabad 500 049, India.
  • 3. Curis Inc., 4 Maguire Road, Lexington, Massachusetts 02421, United States.
PMID: 33335659 DOI: 10.1021/acsmedchemlett.0c00255
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.