Abstract 1713: Novel, potent and orally bioavailable small molecule CD73 inhibitors for cancer immunotherapy

Autor: Girish Daginakkatte, Kavitha Nellore, Sunil Kumar Panigrahi, Sagar dadhania, AB Aravind, Thomas Antony, Megha Goyal, Murali Ramachandra, DS Samiulla, Prasath Kothandaraman, Susanta Samajdar, Dinesh Chikkanna, Rashmi Nair, Kishore Narayanan, Chandregowda Venkateshappa, Garima Priyadarshani, Vijay Kamal Ahuja
Rok vydání: 2021
Předmět:
Zdroj: Cancer Research. 81:1713-1713
ISSN: 1538-7445
0008-5472
DOI: 10.1158/1538-7445.am2021-1713
Popis: CD73 is a cell surface ectoenzyme, which is overexpressed in many types of human and mouse cancers. CD73 is the primary enzymatic producer of immunosuppressive adenosine in the tumor microenvironment, and high CD73 expression is associated with significantly poorer prognosis in several tumor types. Inhibition of either adenosine generation or signaling by inhibiting CD73 have been shown to be effective therapeutic approaches. Here we sought to discover and develop novel and orally bioavailable small molecule inhibitors that target CD73. Aurigene's non-nucleotide small molecule exhibit potent inhibition of CD73 in respective biochemical and cellular assays. High potency translated into rescue of AMP induced repression of IFN-Υ and IL-2 in human PBMCs. Lead compounds exhibited desirable drug-like properties including solubility, Caco2 permeability, lack of CYP inhibition and excellent oral pharmacokinetic exposure. In summary, we have identified small molecule inhibitors with good drug like properties, which showed good in vitro potency and excellent PK. Evaluation of these lead compounds in syngeneic tumor model along with in vivo toxicity studies are currently under way. Citation Format: Chandregowda Venkateshappa, Kishore Narayanan, Prasath Kothandaraman, Garima Priyadarshani, Rashmi Nair, Megha Goyal, Vijay Kamal Ahuja, Sagar Dadhania, AB Aravind, DS Samiulla, Girish Daginakkatte, Thomas Antony, Kavitha Nellore, Sunil Panigrahi, Dinesh Chikkanna, Susanta Samajdar, Murali Ramachandra. Novel, potent and orally bioavailable small molecule CD73 inhibitors for cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1713.
Databáze: OpenAIRE
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