COMPOSITIONS FOR INHIBITING RIBOSOME INACTIVATING PROTEINS (RIPs), METHODS OF IDENTIFYING SAME, AND METHODS OF USE THEREOF

A compound of Formula (II) or a pharmaceutically acceptable salt thereof:

• wherein:
• L1 is selected from the group consisting of a bond and optionally substituted C1-C2 alkylenyl;
• R1 is a carboxylic acid (—COOH), —C(═O)ORA, —[C(═O)]3RA, —C(═O)C(OH)2C(═O)ORA, —C(═O)NHORA, H, a carboxylic acid bioisostere, or a carboxylic acid precursor;
• R2a and R2b are each independently H or optionally substituted C1-C6 alkyl;
• R3a, R3b, and R3c are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C6-C10 aryl, optionally substituted C2-C8 heteroaryl, halogen, CN, NO2, ORA, N(RA)(RB), C(═O)RA, C(═O)ORA, C(═O)N(RA)(RB), N(RA)C(═O)RB, S(═O)2RA, S(═O)2N(RA)(RB), S(═O)2ORA, and N(RA)S(═O)2RB;
• R6a and R6b are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C6-C10 aryl, optionally substituted C2-C8 heteroaryl, C(═O)RA, and
• L2 is selected from the group consisting of
• R7 is selected from the group consisting of
• R8a and R8b are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, and optionally substituted C3-C8 cycloalkyl, or R8a and R8b can combine with the atoms to which they are bound to form an optionally substituted C2-C8 heterocycloalkyl;
• R9a and R9b are each independently selected from the group consisting of H and optionally substituted C1-C6 alkyl;
• R10a, R10b, and R10c are each independently selected from the group consisting of optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C6-C10 aryl, optionally substituted C6-C8 heteroaryl, halogen, C(═O)RA, C(═O)ORA, C(═O)N(RA)(RB), S(═O)RA, S(═O)2RA, S(═O)N(RA)(RB), and S(═O)2N(RA)(RB), or two vicinal substituents selected from the group consisting of R10a, R10b, and R10c can combine with the atoms to which they are bound to form an optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted C6-C10 aryl, or optionally substituted C2-C8 heteroaryl;
• each occurrence of RA and RB is independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C6-C10 aryl, optionally substituted C2-C8 heteroaryl;
• wherein one of the following applies:
• (a) R6a and R6b are each optionally substituted C1-C6 alkyl, wherein no more than one of R6a and R6b is optionally substituted C1 alkyl;
• (b) one of R6a and R6b is methyl, and one of R6a and R6b is selected from the group consisting of optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted phenyl, and C1-C6 alkyl, wherein the optionally substituted alkyl is substituted with at least one optionally substituted phenyl;
• (c) one of R6a and R6b is methyl, one of R6a and R6b is H, and one of R3a and R3c is selected from the group consisting of optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted phenyl, and C1-C6 alkyl;
• (d) one of R6a and R6b is H, and one of R6a and R6b is selected from the group consisting of C1-C6 alkyl, optionally substituted C1-C6 haloalkoxy, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, and C(═O)H, wherein the C1-C6 alkyl is substituted with at least one substituent selected from the group consisting of C2-C8 alkynyl, C1-C6 alkoxy, C═O, and CN;
• and
• (e) one of R6a and R6b is

A method for measuring binding affinity of a small molecule for an active A chain (RTA) of a ribosome inactivating protein (RIP), the method comprising:

• (a) contacting a small molecule with a mixture comprising a fluorescently labeled P11 polypeptide (SEQ ID NO:1) and RTA to provide a displacing mixture;
• (b) measuring fluorescence of the displacing mixture to provide a displaced fluorescence mixture;
• (c) measuring fluorescence of a control sample comprising the fluorescently labeled P11 polypeptide (SEQ ID NO:1) and RTA, and lacking the small molecule, to provide a control measurement;
• and
• (d) comparing the displaced fluorescence measurement and the control fluorescence measurement.