Modified amatoxins and uses thereof

An amatoxin analog comprising at least one of the following eastern ring residues:

• (a) a Gly5 residue of the formula:
• wherein X1 is (CH2)m, CHCH3, CHCH2CH3, C(CH3)2 or NR′;
• (b) an Ile6 residue of the formula:
• wherein R1 is CH(Z—CH3)2, wherein one or more available hydrogens is/are optionally substituted with SH;
• or R1 is C3-10cycloalkyl, wherein one or more available hydrogens on the C3-10cycloalkyl is/are optionally substituted with C1-10alkyl and/or one or more available carbon atoms in the C3-10cycloalkyl is/are optionally replaced by O or S;
• each Z is independently (CH2)mO(CH2)p, (CH2)nS(CH2)p, (CH2)nSe(CH2)p or (CH2)q;
• each n is independently an integer from 0 to 4;
• each p is independently an integer from 0 to 4;
• n+p in each Z, is independently ≤4;
• each q is independently an integer from 0 to 4;
• and
• wherein one or more single bonds between two available carbon atoms in R1 is/are optionally replaced by a double bond;
• (c) a Gly7 residue of the formula:
• wherein X2 is (CH2)m, CHCH3, CHCH2CH3, C(CH3)2 or NR′;
• and
• (d) a Cys8 residue of the formula:
• wherein
• A is S, S(O), SO2, Se, Se(O) or SeO2;
• and
• R2a and R2b are each independently H or C1-10alkyl;
• or R2a and R2b together with the carbon atom to which they are attached, together form C3-10cycloalkyl;
• each m is independently an integer from 1 to 5;
• and
• each R′ is independently H, C1-20alkyl, C2-20alkenyl, C2-20alkynyl, C3-20cycloalkyl, C6-30aryl, heterocycloalkyl or heteroaryl, wherein one or more available carbon atoms in the C1-20alkyl, C2-20alkenyl and C2-20alkynyl is optionally replaced by a heteroatom, and wherein the C1-20alkyl, C2-20alkenyl, C2-20alkynyl, C3-20cycloalkyl, C6-30aryl, heterocycloalkyl and heteroaryl is optionally further substituted with one or more groups selected from OR″, SR″, halo, azide and nitrile, wherein R″ is independently H, C1-20alkyl, C2-20alkenyl, C2-20alkynyl, C3-20cycloalkyl, C6-30aryl, heterocycloalkyl or heteroaryl,
• or a pharmaceutically acceptable salt thereof,
• provided that the amatoxin analog or the pharmaceutically acceptable salt thereof has one or more of the following:
• (i) R1 other than
• (ii) X1 other than CH2;
• (iii) X2 other than CH2;
• (iv) R2a other than H;
• and
• (v) R2b other than H, and
• wherein in the amatoxin analog or the pharmaceutically acceptable salt thereof, one or more available hydrogens is/are optionally replaced with deuterium and/or one or more available hydrogens is/are optionally replaced with fluorine and/or one or more available atoms is/are optionally replaced with its radioactive isotope.