Peptide compositions targeting glypican-3 and uses thereof

A peptide that has avidity for Glypican 3 (GPC3), or a pharmaceutically acceptable salt thereof, wherein the peptide comprises an amino acid sequence of Formula (I),

• wherein,
• X1 is any amino acid;
• X2 is any amino acid;
• X3 is any amino acid;
• X4 is any amino acid;
• X5 is an amino acid comprising an aromatic ring (e.g., W, F, Y, or a variant thereof), cycloalkyl, or heterocycloalkyl group, or X5 is a peptoid (e.g., Cha4cH, Cha4tH, Almor, Atp, Cha4cOMe);
• X6 is a hydrophobic amino acid, a hydrophilic amino acid, or a polar amino acid wherein the polar amino acid has a substituted side chain;
• X7 is a hydrophobic amino acid comprising a C1-C8 alkyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, cycloalkyl, and heterocycloalkyl are each independently, optionally substituted (e.g., X7 is I, Eva, all, TMe, SMe, Gcpr, Gcpe, Gthp, dMeS, TdMe, or Cbg);
• X8 is a A, I, L, V, Y or F, or a variant thereof;
• X9 is an N-alkylated amino acid comprising an aromatic ring;
• X10 is G, A, or a D-amino acid (e.g, da, ds, de, or dp);
• X11 is an amino acid comprising an aromatic ring (e.g., F, Y, or a variant thereof);
• and,
• X12 is N-alkylated cysteine (e.g., MeC).

A peptide having avidity for Glypican 3 (GPC3), or a pharmaceutically acceptable salt thereof, wherein the peptide has an amino acid sequence of Formula (I),

• wherein,
• X1 is any amino acid;
• X2 is any amino acid;
• X3 is any amino acid;
• X4 is any amino acid;
• X5 is
• wherein:
• Rn5 is hydrogen or C1-3 alkyl;
• ring A5 is an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
• each RX5 is independently C1-6alkyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6aminoalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, halogen, —CN, —NO2, —ORa, —SRa, —SF5, —NRcRd, —S(═O)Ra, —S(═O)2Ra, —S(═O)2NRcRd, —S(═O)(═NRa)Ra, —N═S(═O)NRcRd, —NRaS(═O)2Ra, amidinyl, —NRaC(═NH)NRcRd, —NRaS(═O)2NRcRd, —C(═O)Ra, —C(═O)ORa, —OC(═O)Ra, —OC(═O)ORa, —OC(═O)NRcRd, —NRaC(═O)Ra, —NRaC(═O)ORa, —NRaC(═O)NRcRd, —C(═O)NRcRd, —P(═O)(ORc)(ORd), —P(═O)RcRd, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -LX5-heterocycloalkyl, -LX5-cycloalkyl, -LX5-aryl, or -LX5-heteroaryl, wherein the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more RX5a;
• or
• two RX5 are taken together to form ═O, ═S, or ═N(Ra);
• LX5 is C1-6alkylene, C1-6heteroalkylene, —O—, —S—, or —NRa—, wherein the alkylene and heteroalkylene is optionally substituted with one or more RX5a;
• kx5 is 0, 1, 2, or 3;
• mx5 is 0, 1, 2, 3, 4, or 5;
• *X4 represents the point of attachment to X4;
• and
• *X6 represents the point of attachment to X6;
• X6 is
• wherein;
• Rn6 is hydrogen or C1-3 alkyl;
• RX6 is C1-6alkyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6aminoalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -LX6-heterocycloalkyl, -LX6-cycloalkyl, -LX6-aryl, or -LX6-heteroaryl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more RX6a;
• or
• Rn6 and Rx6 are taken together with the intervening atoms to form a 5- to 6-membered heterocycloalkyl, which is optionally substituted with one or more RX6a;
• LX6 is C1-6alkylene, C1-6heteroalkylene, —O—, —S—, or —NRa—, wherein the alkylene and heteroalkylene is optionally substituted with one or more RX6a;
• *X5 represents the point of attachment to X5;
• and
• *X7 represents the point of attachment to X7;
• X7 is
• wherein:
• Rn7 is hydrogen or C1-3 alkyl;
• RX7 is C1-6alkyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6aminoalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, cycloalkyl, or heterocycloalkyl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more RX7a;
• *X6 represents the point of attachment to X6;
• and
• *X8 represents the point of attachment to X8;
• X8 is
• wherein;
• Rn8 is hydrogen or C1-3alkyl;
• ring A8 is an aryl or heteroaryl;
• each RX8 is independently C1-6alkyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6aminoalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, halogen, —CN, —NO2, —ORa, —SRa, —SF5, —NRcRd, —S(═O)Ra, —S(═O)2Ra, —S(═O)2RcRd, —S(═O)(═NRa)Ra, —N═S(═O) RcRd, —NRaS(═O)2Ra, amidinyl, —NRaC(═NH)NRcRd, —NRaS(═O)2RcRd, —C(═O)Ra, —C(═O)ORa, —OC(═O)Ra, —OC(═O)ORa, —OC(═O)NRcRd, —NRaC(═O)Ra, —NRaC(═O)ORa, —NRaC(═O)NRcRd, —C(═O)NRcRd, —P(═O)(OR)(ORd), —P(═O)RcRd, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -LX8-heterocycloalkyl, -LX8-cycloalkyl, -LX8-aryl, or -LX8-heteroaryl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more RX8a;
• or
• two RX8 are taken together to form ═O, ═S, or ═N(Ra);
• LX8 is C1-6alkylene, C1-6heteroalkylene, —O—, —S—, or —NRa—, wherein the alkylene and heteroalkylene is optionally substituted with one or more RX8a;
• kx8 is 0, 1, 2, or 3;
• mx8 is 0, 1, 2, 3, 4, or 5;
• *X7 represents the point of attachment to X7;
• and
• *X9 represents the point of attachment to X9;
• X9 is
• wherein:
• Rn9 is hydrogen or C1-3 alkyl;
• ring A9 is an aryl or heteroaryl;
• each RX9 is independently C1-6alkyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6aminoalkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, halogen, —CN, —NO2, —ORa, —SRa, —SF5, or —NRcRd, wherein each of the alkyl, heteroalkyl, alkenyl, and alkynyl is optionally substituted with one or more RX9a;
• or
• two RX9 are taken together to form ═O, ═S, or ═N(Ra);
• kx9 is 0, 1, 2, or 3;
• mx9 is 0, 1, 2, 3, 4, or 5;
• *X8 represents the point of attachment to X8;
• and
• *X10 represents the point of attachment to X10;
• X10 is glycine or a D-amino acid (e.g., da, ds, de, or dp);
• X11 is
• wherein:
• Rn11 is hydrogen or C1-3 alkyl;
• ring A11 is an aryl or heteroaryl;
• each RX11 is independently C1-6alkyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6aminoalkyl, C1-6heteroalkyl, halogen, —CN, —NO2, —ORa, —SRa, —SF5, —NRcRd, —S(═O)Ra, —S(═O)2Ra, —S(═O)2RcRd, —S(═O)(═NRa)Ra, —N═S(═O)RcRd, —NRaS(═O)2Ra, amidinyl, —NRaC(═NH)NRcRd, —NRaS(═O)2RcRd, —C(═O)Ra, —C(═O)ORa, —OC(═O)Ra, —OC(═O)ORa, —OC(═O)NRcRd, —NRaC(═O)Ra, —NRaC(═O)ORa, —NRaC(═O)NRcRd, —C(═O)NRcRd, —P(═O)(ORc)(ORd), —P(═O)RcRd, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -LX11-heterocycloalkyl, -LX11-cycloalkyl, -LX11-aryl, or -LX11-heteroaryl, wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more RX11a;
• or
• two RX11 are taken together to form ═O, ═S, or ═N(Ra);
• LX11 is C1-6alkylene, C1-6heteroalkylene, —O—, —S—, or —NRa—, wherein the alkylene and heteroalkylene is optionally substituted with one or more RX11a;
• kx11 is 0, 1, 2, 3, 4, or 5;
• mx11 is 0, 1, 2, 3, 4, or 5;
• *X10 represents the point of attachment to X10;
• and,
• *X12 represents the point of attachment to X12;
• X12 is N-alkylated cysteine;
• each of RX5a, RX6a, RX7a, RX8a, RX9a, and RX11a is independently halogen, C1-6 alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C5alkenyl, C2-C5alkynyl, —CN, —NO2, —ORa, —SRa, —NRcRd, —S(═O)Ra, —S(═O)2Ra, —SF5, —S(═O)2NRcRd, —S(═O)(═NRa)Ra, —N═S(═O)RcRd, —NRaS(═O)2Ra, amidinyl, —NRaC(═NH)(NRa)2, —NRaS(═O)2NRcRd, —C(═O)Ra, —C(═O)ORa, —OC(═O)Ra, —OC(═O)ORa, —OC(═O)NRcRd, —NRaC(═O)Ra, —NRaC(═O)ORa, —NRaC(═O)NRcRd, —C(═O)NRcRd, —P(═O)(ORc)(ORd), —P(═O)RcRd, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, ═O, ═S, or ═N(Ra), wherein each of the alkyl, heteroalkyl, alkenyl, and alkynyl is optionally substituted with one or more Re.
• each Ra is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Re;
• each Re is independently halogen, —CN, —OH, —O—C1-C6alkyl, —SF5, —S(═O)C1-C6alkyl, —S(═O)2C1-C6alkyl, —S(═O)2NH2, —S(═O)2-halogen, —S(═O)2NHC1-C6alkyl, —S(═O)2N(C1-C6alkyl)2, —NH2, —NHC1-C6alkyl, —N(C1-C6alkyl)2, —NHC(═NH)NH2, —NHC(═O)OC1-C6alkyl, —C(═O)C1-C6alkyl, —C(═O)OH, C1-C6alkyl-C(═O)OH, —C(═O)OC1-C6alkyl, —C(═O)NH2, —C(═O)N(C1-C6alkyl)2, —C(═O)NHC1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl;
• or two Re are taken together to form ═O;
• and
• each Rc and Rd are independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Re;
• or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more Re.