Hemiasterlin derivatives for conjugation and therapy
Provided herein are hemiasterlin derivatives, conjugates thereof, compositions comprising the derivatives or conjugates thereof, methods of producing the derivatives and conjugates thereof, and methods of using the derivatives, conjugates, and compositions for the treatment of cell proliferation. The derivatives, conjugates, and compositions are useful in methods of treatment and prevention of cell proliferation and cancer, methods of detection of cell proliferation and cancer, and methods of diagnosis of cell proliferation and cancer. In an embodiment, the hemiasterlin derivatives are according to Formula 1000: or a pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein Ar, L, W 1 , W 4 , W 5 , SG, and R are as described herein.
1. A compound according to Formula 1000:
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:
Ar is a divalent six-membered, substituted or unsubstituted, monocyclic aryl; a divalent five- or six-membered, substituted or unsubstituted, monocyclic heteroaryl; a divalent nine- or ten-membered, substituted or unsubstituted, fused bicyclic aryl; or a divalent eight-, nine- or ten-membered, substituted or unsubstituted, fused bicyclic heteroaryl;
L is absent or —CH 2 —;
W 1 , W 2 , W 3 , W 4 , W 5 are each independently, a single bond, absent, or a divalent attaching group;
EG is;
wherein each R EG is independently selected from the group consisting of hydrogen, alkyl, biphenyl, —CF 3 , —NO 2 , —CN, fluoro, bromo, chloro, alkoxyl, alkylamino, dialkylamino, alkyl-C(O)O—, alkylamino-C(O)— and dialkylaminoC(O)-;
each RT is a release trigger group, in the backbone of Formula 1000 or bonded to EG, wherein each RT is optional;
RT 1 is a release trigger group, or a cleavable linker, or RT 1 is absent;
HP is a single bond, absent, or a divalent hydrophilic group;
HP 1 is a single bond, absent, a divalent hydrophilic group, or where R HP is a monovalent hydrophilic group;
SG is a single bond, absent, or a divalent spacer group; and
R is:
—N 3 , or —SH;
wherein R 201 is lower alkyl.
2. The compound of claim 1 according to Formula I:
or a pharmaceutically acceptable salt, or tautomer thereof.
3. The compound of claim 2 , wherein one RT is optional and RT comprises a natural or non-natural amino acid or a sugar; or a pharmaceutically acceptable salt, or tautomer thereof.
4. The compound of claim 2 , wherein one RT is optional and RT is:
or a pharmaceutically acceptable salt, or tautomer thereof.
5. The compound of claim 4 , wherein SG comprises C 1 —C 10 alkylene, —C(O)—, or a combination thereof; or a pharmaceutically acceptable salt, or tautomer thereof.
6. The compound of claim 2 , wherein SG is:
or a pharmaceutically acceptable salt, or tautomer thereof.
7. The compound of claim 2 , wherein HP is:
wherein m is an integer selected from 1 to 12; or a pharmaceutically acceptable salt, or tautomer thereof.
8. The compound of claim 2 where W 1 , W 2 , W 3 , W 4 and W 5 are independently absent or a bond; or a pharmaceutically acceptable salt, or tautomer thereof.
9. The compound of claim 2 wherein Ar is a divalent six-membered, substituted or unsubstituted, monocyclic aryl or a divalent six-membered, substituted or unsubstituted, monocyclic heteroaryl; or a pharmaceutically acceptable salt, or tautomer thereof.
10. The compound of claim 1 according to Formula 1001 or 1002:
or a pharmaceutically acceptable salt, or tautomer thereof, wherein
RT 1 is a release trigger group or a cleavable linker; and
RT is optional.
11. The compound of claim 1 , wherein RT 1 is absent;
valine-alanine; valine-glutamic acid; alanine-phenylalanine; phenylalanine-lysine; phenylalanine-homolysine; glycine-glycine-glycine;
where aa is a natural or non-natural amino acid residue; or
where the ring is a 4-7 membered heterocyclic ring comprising 3-6 carbon atoms; or a pharmaceutically acceptable salt, or tautomer thereof.
12. The compound of claim 1 , wherein R 201 is methyl, ethyl, or propyl; or a pharmaceutically acceptable salt, or tautomer thereof.
13. The compound of claim 1 , wherein W 1 , W 2 , W 3 , W 4 , and W 5 are each independently a single bond, absent, or comprise C(O)—, —O —, —C(O)NH—, —C(O)NH-alkyl—, —OC(O)NH—, —SC(O)NH—, —NH—, —NH-alkyl—, —N(CH 3 )CH 2 CH 2 N(CH 3 )—, —S—, —S—S—, —OCH 2 CH 2 O—, or a combination thereof; or a pharmaceutically acceptable salt, or tautomer thereof.
14. The compound of claim 1 , wherein Ar is a divalent nine-membered, substituted or unsubstituted, fused bicyclic heteroaryl; or a pharmaceutically acceptable salt, or tautomer thereof.
15. The compound of claim 1 , wherein L is absent; or a pharmaceutically acceptable salt, or tautomer thereof.
16. The compound of claim 1 , according to any of the following Formulas:
or a pharmaceutically acceptable salt, or tautomer thereof.