Discovery of LYC-55716: A Potent, Selective, and Orally Bioavailable Retinoic Acid Receptor-Related Orphan Receptor-γ (RORγ) Agonist for Use in Treating Cancer

Abstract

Retinoic acid receptor-related orphan receptor γ (RORc, RORγ, or NR1F3) is the nuclear receptor master transcription factor that drives the function and development of IL-17-producing T helper cells (Th17), cytotoxic T cells (Tc17), and subsets of innate lymphoid cells. Activation of RORγ+ T cells in the tumor microenvironment is hypothesized to render immune infiltrates more effective at countering tumor growth. To test this hypothesis, a family of benzoxazines was optimized to provide LYC-55716 (37c), a potent, selective, and orally bioavailable small-molecule RORγ agonist. LYC-55716 decreases tumor growth and enhances survival in preclinical tumor models and was nominated as a clinical development candidate for evaluation in patients with solid tumors.

Discovery of Biaryl Amide Derivatives as Potent, Selective, and Orally Bioavailable RORγt Agonists for Cancer Immunotherapy

“…Importantly, compound 14 exhibited remarkable oral bioavailability with values of 90.3 and 52.2% in mouse and dog, respectively. In contrast, the Phase II compound LYC-55716 had an oral bioavailability of 55% in mouse . According to its great oral bioavailability in different species, compound 14 was selected as lead compound for further in vivo antitumor efficacy evaluation.…”

“…In contrast, the Phase II compound LYC-55716 had an oral bioavailability of 55% in mouse. 25 According to its great oral bioavailability in different species, compound 14 was selected as lead compound for further in vivo antitumor efficacy evaluation.…”

“…RORγt can accelerate the activation and differentiation of CD4 + and CD8 + T cells into Th17 cells and IL-17-secreting CD8 + T cells (Tc17) and then produce pro-inflammatory cytokines like IL-17 . It has been demonstrated that RORγt agonists enhance T-cell effector functions and decrease immune-suppressive mechanisms, leading to improved antitumor efficacy. , In clinical practice, cintirorgon (LYC-55716), an oral small-molecule RORγt agonist under development by Lycera, has completed Phase I/II trial for the treatment of solid tumors in 2019. , Therefore, RORγt agonists remain potential tactics to cancer immunotherapy as orally bioavailable small-molecule therapeutics …”

“…22,23 In clinical practice, cintirorgon (LYC-55716), an oral small-molecule RORγt agonist under development by Lycera, has completed Phase I/II trial for the treatment of solid tumors in 2019. 24,25 Therefore, RORγt agonists remain potential tactics to cancer immunotherapy as orally bioavailable small-molecule therapeutics. 26 In addition to LYC-55716, a number of RORγt agonists with diverse scaffolds have been disclosed (Figure 1), including Narylsulfonyl indolines by Scripps Research Institute, 27 benzyloxytricyclic compounds by Bristol Myers Squibb, 28 2-(ortho-substituted benzyl)-indoles from Shanghai Hengrui, 29 tertiary amines 30 and biaryl series 31 from GSK, and so on.…”

Tandem Allylic Amination/oxa-Michael Addition of Vinyl Methylene Cyclic Carbonates via Palladium-Organo Relay Catalysis

“…It is worth mentioning that 3,4-dihydro-2H-benzo[b] [1,4]oxazine with a 2-stereocenter is one of the important N,O-heterocyclic compounds, which has been widely present in drug candidates, as shown in Scheme 2. 8 Therefore, many efficient synthetic methods have been developed by synthetic chemists. 9…”