Formulations for modulating myc expression

A composition comprising:

• (1) a nucleic acid (e.g., RNA, e.g., mRNA) encoding an expression repressor, wherein the expression repressor comprises:
• (a) a first targeting moiety that binds a genomic locus comprising at least 16, 17, 18, 19, or 20 nucleotides of the sequence of any of SEQ ID NOs:
• 83, 2, 3, 75-86, 97-107, 109, 110, 190-192, or 199-202, and
• (b) optionally, a first effector moiety,
• wherein the expression repressor is capable of decreasing expression of MYC;
• and
• (2) a formulation comprising one or both of:
• (i) a first compound having a general structure of formula (I)
• or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof,
• wherein L1 and L2 are each independently —O(C═O)—, —(C═O)O—, —C(═O)—, —O—, —S(O)x—, —S—S—, —C(═O)S—, SC(═O)—, —NRaC(═O)—, —C(═O)NRa—, —NRaC(═O)NRa—, —OC(═O)NRa—, —NRaC(═O)O—, or a direct bond;
• G1 and G2 are each independently unsubstituted C1-C12 alkylene or C2-C12 alkenylene;
• G3 is C1-C24 alkylene, C2-C24 alkenylene, C3-C8 cycloalkylene, C3-C8 cycloalkenylene;
• Ra is H or C1-C12 alkyl;
• R1 and R2 are each independently C6-C24 alkyl or C6-C24 alkenyl;
• R3 is H, OR5, CN, —C(═O)OR4, —OC(═O)R4, —NR11R12, or —NR5C(═O)R4;
• R4 is C1-C12 alkyl;
• R5 is H or C1-C6 alkyl;
• R11 and R12 are each independently C1-C12 alkyl or -G4-OR5, or R11 and R12, together with the nitrogen atom to which they are attached, form a 5, 6 or 7-membered heterocyclic ring;
• G4 is C1-C24 alkylene, C2-C24 alkenylene, C3-C8 cycloalkylene, C3-C8 cycloalkenylene;
• and
• x is 0, 1 or 2;
• and
• (ii) a second compound having a general structure of formula (II):
• or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof,
• wherein R6 and R7 are each independently a straight or branched, saturated or unsaturated alkyl chain containing from 10 to 30 carbon atoms, wherein the alkyl chain is optionally interrupted by one or more ester bonds;
• and
• y has mean value ranging from 30 to 60.

The composition of any of the preceding claims, wherein the first compound has a general structure of formula (III):

• or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof,
• wherein L1 and L2 are each independently —(C═O)O— or —O(C═O)—;
• R1 and R2 are each independently C6-C24 alkyl or C6-C24 alkenyl;
• R3 occurs once and is H, OR5, CN, —C(═O)OR4, —OC(═O)R4 or —NR5C(═O)R4;
• R4 is C1-C12 alkyl;
• R5 is H or C1-C6 alkyl;
• R occurs n times and is, at each occurrence, independently H, OH or C1-C24 alkyl;
• n is an integer ranging from 1 to 15;
• and m and 1 are each independently integers ranging from 1 to 12.

A composition comprising:

• (1) a nucleic acid (e.g., RNA, e.g., mRNA) encoding an expression repressor, wherein the expression repressor comprises:
• (a) a targeting moiety that binds to a MYC promoter or a genomic locus comprising at least 16, 17, 18, 19, or 20 nucleotides of the sequence of any of SEQ ID NOs:
• 83, 2, 3, 75-86, 97-107, 109, 110, 190-192, or 199-202, and
• (b) optionally, an effector moiety,
• wherein the expression repressor is capable of decreasing expression of MYC;
• and
• (2) a formulation comprising one or both of:
• (i) a first compound having a general structure of formula (IX)
• or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein:
• L1 and L2 are each independently —O(C═O)—, —(C═O)O—, —C(═O)—, —O—, —S(O)x—, —S—S—, —C(═O)S—, —SC(═O)—, —NRaC(═O)—, —C(═O)NRa—, —NRaC(═O)NRa—,
• —OC(═O)NRa—, —NRaC(═O)O— or a direct bond;
• G′ is C1-C2 alkylene, —(C═O)—, —O(C═O)—, —SC(═O)—, —NRaC(═O)— or a direct bond;
• G2 is —C(═O)—, —(C═O)O—, —C(═O)S—, —C(═O)NRa— or a direct bond;
• G3 is C1-C6 alkylene;
• Ra is H or C1-C12 alkyl;
• R1a and R1b are, at each occurrence, independently either:
• (a) H or C1-C12 alkyl;
• or (b) R1a is H or C1-C12 alkyl, and R1b together with the carbon atom to which it is bound is taken together with an adjacent R1b and the carbon atom to which it is bound to form a carbon-carbon double bond;
• R2a and R2b are, at each occurrence, independently either:
• (a) H or C1-C12 alkyl;
• or (b) R2a is H or C1-C12 alkyl, and R2b together with the carbon atom to which it is bound is taken together with an adjacent R2b and the carbon atom to which it is bound to form a carbon-carbon double bond;
• R3a and R3b are, at each occurrence, independently either:
• (a) H or C1-C12 alkyl;
• or (b) R3a is H or C1-C12 alkyl, and R3b together with the carbon atom to which it is bound is taken together with an adjacent R3b and the carbon atom to which it is bound to form a carbon-carbon double bond;
• R4a and R4b are, at each occurrence, independently either:
• (a) H or C1-C12 alkyl;
• or (b) R4a is H or C1-C12 alkyl, and R4b together with the carbon atom to which it is bound is taken together with an adjacent R4b and the carbon atom to which it is bound to form a carbon-carbon double bond;
• R5 and R6 are each independently H or methyl;
• R7 is C4-C20 alkyl;
• R8 and R9 are each independently C1-C12 alkyl;
• or R8 and R9, together with the nitrogen atom to which they are attached, form a 5, 6 or 7-membered heterocyclic ring;
• a, b, c and d are each independently an integer from 1 to 24;
• and
• x is 0, 1 or 2;
• and
• (ii) a second compound having a general structure of formula (II):
• or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof,
• wherein R6 and R7 are each independently a straight or branched, saturated or unsaturated alkyl chain containing from 10 to 30 carbon atoms, wherein the alkyl chain is optionally interrupted by one or more ester bonds;
• and
• y has mean value ranging from 30 to 60.

A composition comprising:

• (1) a nucleic acid (e.g., RNA, e.g., mRNA) encoding an expression repressor, wherein the expression repressor comprises:
• (a) a targeting moiety that binds to a MYC promoter or a genomic locus comprising at least 16, 17, 18, 19, or 20 nucleotides of the sequence of any of SEQ ID NOs:
• 83, 2, 3, 75-86, 97-107, 109, 110, 190-192, or 199-202, and
• (b) optionally, an effector moiety,
• wherein the expression repressor is capable of decreasing expression of MYC;
• and
• (2) a formulation comprising one or both of:
• (i) a first compound having a general structure of formula (XI)
• or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein:
• R1 is optionally substituted C1-C24 alkyl or optionally substituted C2-C24 alkenyl;
• R2 and R3 are each independently optionally substituted C1-C36 alkyl;
• R4 and R are each independently optionally substituted C1-C6 alkyl, or R4 and R join, along with the N to which they are attached, to form a heterocyclyl or heteroaryl;
• L1, L2, and L3 are each independently optionally substituted C1-C15 alkylene;
• G1 is a direct bond, —(CH2)nO(C═O)—, —(CH2)n(C═O)O—, or —(C═O)—;
• G2 and G3 are each independently —(C═O)O— or —O(C═O)—;
• and
• n is an integer greater than 0;
• and
• (ii) a second compound having a general structure of formula (II):
• or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof,
• wherein R6 and R7 are each independently a straight or branched, saturated or unsaturated alkyl chain containing from 10 to 30 carbon atoms, wherein the alkyl chain is optionally interrupted by one or more ester bonds;
• and
• y has mean value ranging from 30 to 60.