1341 Discovery and preclinical characterization of ALG-093940, a potent and orally bioavailable small molecule PD-L1 inhibitor for the treatment of cancer
Year: 2024
Type: conference-abstract
Abstract: Background PD-1/PD-L1 antibody-based therapies have demonstrated tremendous success in the treatment of a variety of cancers. However, these antibody drugs are associated with several disadvantages, such as weak tumor penetration, immune-related adverse events (irAEs) due to their long half-life and development of anti-drug antibodies. Recently, PD-L1 small molecule inhibitors have been developed, e.g., INCB086550 that demonstrated clinical responses in a phase I study.1 Here, we report the discovery and preclinical characterization of ALG-093940, a potent and orally bioavailable small molecule PD-L1 inhibitor, that may overcome the limitations of PD-1/PD-L1 antibodies. Methods The biochemical interaction of PD-1/PD-L1 and PD-L1 dimerization was assessed by AlphaLISA®. Cellular activity was measured using a co-culture assay of PD-1 expressing Jurkat NFAT luciferase T cells with PD-L1 expressing CHO cells. In vitro ADME and the compound safety profile was established using standard assays. Pharmacokinetic (PK) studies were performed in mice, rat and cynomolgus monkey. In vivo inhibition of tumor growth, PD-L1 target occupancy and tumor infiltration of T-cells were assessed in a humanized-PD-L1 MC38 subcutaneous tumor mouse model. Results ALG-093940 inhibited PD-1/PD-L1 interaction with an IC50 of 0.048 nM and induced PD-L1 dimerization with an EC50 of 79 nM. ALG-093940 showed comparable T-cell activation potency to INCB086550. ALG-093940 demonstrated no in vitro liabilities for CYP-mediated drug-drug interactions, cardiovascular safety, or genotoxicity and exhibited low clearance (5.3 – 12 mL/minute/kg) and moderate to high oral bioavailability (58 - >100%) in preclinical species, indicating its potential for once daily dosing in patients. In the in vivo humanized-PD-L1 MC38 mouse model, oral once daily dosing of ALG-093940 at 1.5, 15, 50 or 150 mg/kg demonstrated dose-dependent inhibition of tumor growth with tumor stasis and tumor regression observed in a subset of animals. At 24 hours post-final dose on day 21, PD-L1 target engagement demonstrated dose-dependent increases up to 98%. In addition, dose-dependent increases in tumor-infiltration of CD8+ T-cells and CD8+/CD4+ T-cell ratios were observed. All 21-day dosing regimens were well tolerated with body weight gains indistinguishable between ALG-093940 and vehicle treated animals. Conclusions ALG-093940 is a potent PD-L1 small molecule inhibitor, that shows similar T-cell activation potency to INCB086550. ALG-093940 demonstrated excellent, dose-dependent tumor growth inhibition, target engagement and tumor T-cell infiltration in a humanized PD-L1 MC38 subcutaneous mouse model. The properties of ALG-093940 warrant further development as a potential clinical candidate for the treatment of cancer. Reference Koblish HK, Wu L, Wang LS, et al. Characterization of INCB086550: a potent and novel small-molecule PD-L1 inhibitor. Cancer Discov. 2022;12(6):1482–1499.
Authors: Heleen Roose, Kristina Rekstyte-Matiene, Sarah Stevens, Kusum Gupta, Sandra Chang, Cheng Liu, Vladimir Serebryany, Lillian Adame, Kha Le, Antitsa Stoycheva, Dinah Misner, Lawrence M Blatt, Leonid Beigelman, Sushmita Chanda, David B Smith, Julian A Symons, Andreas Jekle, Tongfei Wu
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
OpenAlex ID: W4404065561