PD-1/PD-L1 inhibitors
Inventors
Aktoudianakis, Evangelos • Cho, Aesop • Graupe, Michael • Lad, Lateshkumar Thakorlal • Machicao Tello, Paulo A. • Medley, Jonathan William • Metobo, Samuel E. • NADUTHAMBI, DEVAN • Phillips, Barton W. • Simonovich, Scott Preston • Wang, Peiyuan • Watkins, William J. • Xu, Jie • Yang, Kin Shing • Ziebenhaus, Christopher Allen
Assignees
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Publication Number
US-12269812-B2
Publication Date
2025-04-08
Expiration Date
Abstract
Compounds and methods of using said compounds singly or in combination with additional agents and compositions of said compounds for the treatment of cancer are disclosed.
Core Innovation
The invention relates to compounds of formula (IIA), or pharmaceutically acceptable salts thereof. The compound class defines multiple atom positions and substituents, including X1, X2, X3, and X4 selected from N, CH, or CZ3, and Z1 selected from halo, —ORa, cyano, or —C1-6 alkyl, with each Z3 independently selected from enumerated halo, —ORa, —N3, —NO2, cyano, —NR1R2, —SO2Ra, —SO2NRaRb, —NRaSO2Ra, —NRaC(O)Ra, —C(O)Ra, —C(O)ORa, —C(O)NRaRb, —NRaC(O)ORa, —NRaC(O)NR1R2, —OC(O)NRaRb, and related sulfonyl and carbonyl-containing substituent options. The compound framework further includes optional substitution patterns on alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups.
The formula (IIA) also specifies linker and ring variables, where L1 and L2 are independently a bond, —O—, —NRa—, —S—, —S(O)—, or —S(O)2—, and V is independently selected from a bond, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl. Ring A is independently cycloalkyl, aryl, heteroaryl, or heterocyclyl, each optionally substituted with 1 to 4 groups selected from oxo, —NO2, —N3, —ORa, halo, cyano, —NRaRb, and carbonyl- and sulfonyl-containing groups. The disclosed class is further defined by R1, R2, Ra, Rb, and t variables, including optional combination of R1 and R2 to form a heterocyclyl.
The patent describes broad structural embodiments within the same formula framework, including specific example compounds and formula variants, as well as pharmaceutically acceptable salts, stereoisomers, solvates, and tautomers. The document also references biological content for compounds that inhibit PD-1, PD-L1, and/or the PD-1/PD-L1 interaction, together with compound examples and pharmaceutical composition contexts. The disclosed examples are presented as structural embodiments of the same compound class with variable substitution patterns and related formulations.
Claims Coverage
The provided material centers on an independent compound claim directed to formula (IIA) compounds, or pharmaceutically acceptable salts thereof. A second independent claim is directed to a method of inhibiting PD-1, PD-L1, and/or the PD-1/PD-L1 interaction by administering the claimed compound, and a composition claim includes additional anticancer agents. In total, three inventive features are identified across the independent claims.
Compound of formula (IIA)
A compound of formula (IIA) or a pharmaceutically acceptable salt thereof, wherein X1, X2, X3 and X4 are independently N, CH, or CZ3; Z1 is halo, —ORa, cyano, or —C1-6 alkyl; and each Z3 is independently selected from halo, —ORa, —N3, —NO2, cyano, —NR1R2, —SO2Ra, —SO2NRaRb, —NRaSO2Ra, —NRaC(O)Ra, —C(O)Ra, —C(O)ORa, —C(O)NRaRb, —NRaC(O)ORa, —NRaC(O)NR1R2, —OC(O)NRaRb, and related sulfonyl and carbonyl-containing substituent options.
Inhibiting PD-1/PD-L1 by administration
A method inhibits Programmed death-1 (PD-1), Programmed death-ligand 1 (PD-L1), and/or the PD-1/PD-L1 interaction by administering a compound according to claim 1, or a pharmaceutically acceptable salt thereof, to a patient in need.
Pharmaceutical composition with an additional anticancer agent
A pharmaceutical composition includes the compound together with at least one pharmaceutically acceptable excipient and at least one additional anticancer agent or therapy selected from rituxan, doxorubicin, gemcitabine, nivolumab, pembrolizumab, and ipilimumab.
Claim coverage is anchored by a broad formula (IIA) compound genus with enumerated heteroatom and substituent definitions, together with a PD-1/PD-L1 inhibition method and a pharmaceutical composition that includes additional named anticancer agents.
Stated Advantages
Inhibit PD-1, PD-L1, and/or the PD-1/PD-L1 interaction.
Treat cancer.
Treat hepatitis B virus (HBV).
Therapeutically acts as PD-1/PD-L1/PD-1–PD-L1 interaction inhibitors.
Targets T cell inhibition and exhaustion associated with PD-1/PD-L1 biology.
Induces or stabilizes PD-L1 dimer formation (PD-L1 dimerizing activity).
Provides extensive potency metrics for blocking PD-1/PD-L1 interaction (IC50), PD-1/PD-L1 functional activity via NFAT reporter readout (EC50), and PD-L1/PD-L1 dimerization (AC50) in the documented examples.
GPR4/GRP40 functional assay results indicate selected compounds have no agonist activity and only very weak antagonist activity.
Documented Applications
Treatment of cancer, including named tumor types such as pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, renal cancer, hepatocellular cancer, lung cancer, ovarian cancer, cervical cancer, gastric cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine cancer, CNS cancer, brain cancer, bone cancer, soft tissue sarcoma, non-small cell lung cancer, small-cell lung cancer, colon cancer, lymphoma, multiple myeloma, and leukemia.
Treatment of hepatitis B virus (HBV).
Inhibition of Programmed death-1 (PD-1), Programmed death-ligand 1 (PD-L1), and/or the PD-1/PD-L1 interaction by administering the claimed compound to a patient in need.
A pharmaceutical composition that includes the claimed compound together with at least one additional anticancer agent or therapy selected from rituxan, doxorubicin, gemcitabine, nivolumab, pembrolizumab, and ipilimumab, and a pharmaceutically acceptable excipient.
Biological evaluation of compounds for blocking PD-1/PD-L1 interaction using an ALPHA bead-based PPI assay with IC50 values, and for PD-1/PD-L1 functional activity using an NFAT reporter readout with EC50 values.
Biological evaluation of compounds for PD-L1/PD-L1 dimerization using an ALPHA bead-based assay with AC50 values.
Biological evaluation of selected compounds in a GPR4/GRP40 functional assay indicating no agonist activity and very weak antagonist activity.
Combination use with named additional anticancer agents and checkpoint inhibitors including nivolumab, pembrolizumab, atezolizumab, ipilimumab, rituxan, doxorubicin, and gemcitabine.
Pharmaceutical composition and medicament use, including manufacture and routes of administration such as oral and IV.
Combination therapy for hepatitis B virus (HBV), including administration with HBV DNA polymerase inhibitors and other specified HBV-related agents.
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