HSP90-BINDING CONJUGATES AND FORMULATIONS THEREOF
Conjugates of an active agent attached to a targeting moiety, such as at least one HSP90 binding moiety, via a linker, have been designed. Such conjugates can provide improved temporospatial delivery of the active agent, improved biodistribution and penetration in tumor, and/or decreased toxicity. Methods of making the conjugates and the formulations thereof are provided. Methods of administering the formulations to a subject in need thereof are provided, for example, to treat or prevent cancer.
1 . A conjugate comprising an active agent coupled, via a linker, to at least one targeting moiety (TM), wherein the TM binds to HSP90, wherein the active agent comprises a radioactive agent or a chelating agent for a radioactive agent, and wherein the conjugate the conjugate comprises a structure of Formula X10:
2 . The conjugate of claim 1 , wherein the linker comprises a spacer, wherein the spacer comprises at least one amino acid or analog(s) thereof.
3 . The conjugate of claim 2 , wherein the spacer comprises 2 amino acids or analogs thereof, 3 amino acids or analogs thereof, 4 amino acids or analogs thereof, or 5 amino acids or analogs thereof.
4 . The conjugate of claim 2 , wherein the conjugate comprises a structure of Formula A10:
5 . The conjugate of claim 2 , wherein the TM is selected from TM1, TM2, TM3, TM4, TM5, TM8, TM9, TM10, TM11, TM12, TM13, TM14, TM6, TM7, or TM15.
6 . The conjugate of claim 2 , wherein the conjugate is T1, T2, T4, T5, T6, T8, T9, T10, T27, T28, T29, T39, CMP13, CMP14, CMP15, CMP16, CMP23, CMP37, CMP38, CMP43, CMP44, CMP45, CMP46, CMP47, CMP48, CMP49, CMP50, T1′, T2′, T4′, T5′, T6′, T8′, T9′, T10′, T27′, T28′, T29′, T39′, CMP13′, CMP14′, CMP15′, CMP16′, CMP23′, CMP37′, CMP38′, CMP43′, CMP44′, CMP45′, CMP46′, CMP47′, CMP48′, CMP49′, CMP50′, or a radioactive analog or pharmaceutically acceptable salt thereof.
7 . The conjugate of claim 1 , wherein the linker comprises a spacer, wherein the spacer comprises polyethylene glycol (PEG).
8 . The conjugate of claim 7 , wherein the spacer is (PEG)4 or (PEG)12.
9 . The conjugate of claim 7 , wherein the conjugate comprises a structure of
10 . The conjugate of claim 7 , wherein the TM is selected from TM1, TM2, TM3, TM4, TM5, TM8, TM9, TM10, TM11, TM12, TM13, TM14, TM6, TM7, or TM15.
11 . The conjugate of claim 7 , wherein the conjugate is CMP1, CMP2, CMP29, CMP30, CMP31, CMP32, CMP33, CMP34, CMP35, CMP36, CMP39, CMP40, CMP41, CMP42, CMP52, CMP1′, CMP2′, CMP29′, CMP30′, CMP31′, CMP32′, CMP33′, CMP34′, CMP35′, CMP36′, CMP39′, CMP40′, CMP41′, CMP42′, CMP52′, or a radioactive analog or pharmaceutically acceptable salt thereof.
12 . The conjugate of claim 1 , wherein the conjugate comprises at least one pharmacokinetic modulating unit (PMU).
13 . The conjugate of claim 12 , wherein the PMU binds to albumin.
14 . The conjugate of claim 13 , wherein the PMU comprises
15 . The conjugate of claim 12 , wherein the conjugate comprises a structure of
16 . The conjugate of claim 12 , wherein the TM is selected from TM1, TM2, TM3, TM4, TM5, TM8, TM9, TM10, TM11, TM12, TM13, TM14, TM6, TM7, or TM15.
17 . The conjugate of claim 12 , wherein the conjugate is CMP3, CMP4, CMP5, CMP6, T3, T7, T11, T12, T13, T14, T15, T16, T17, T22, T23, T32, T24, T33, T34, T35, T36, T37, T38, T41, T42, CMP3′, CMP4′, CMP5′, CMP6′, T3′, T7′, T11′, T12′, T13′, T14′, T15′, T16′, T17′, T22′, T23′, T32′, T24′, T33′, T34′, T35′, T36′, T37′, T38′, T41′, T42′, or a radioactive analog or pharmaceutically acceptable salt thereof.
18 . The conjugate of claim 1 , wherein the TM is selected from TM1, TM2, TM3, TM4, TM5, TM8, TM9, TM10, TM11, TM12, TM13, TM14, TM6, TM7, or TM15.
19 . The conjugate of claim 1 , wherein the conjugate is CMP7, CMP8, CMP9, CMP10, CMP 11, CMP12, CMP17, CMP18, CMP19, CMP20, CMP21, CMP22, CMP24, CMP25, CMP26, CMP27, CMP28, T18, T19, T20, T21, T25, T26, T30, T31, T43, T40, CMP7′, CMP8′, CMP9′, CMP10′, CMP11′, CMP12′, CMP17′, CMP18′, CMP19′, CMP20′, CMP21′, CMP22′, CMP24′, CMP25′, CMP26′, CMP27′, CMP28′, T18′, T19′, T20′, T21′, T25′, T26′, T30′, T31′, T43′, T40′, or a radioactive analog or pharmaceutically acceptable salt thereof.
20 . A pharmaceutical composition comprising the conjugate of claim 1 and at least one pharmaceutically acceptable excipient.
21 . A method of reducing cell proliferation comprising administering a therapeutically effective amount of at least one conjugate of claim 1 to the cell.
22 . The method of claim 21 , wherein the cell is a cancer cell.
23 . The method of claim 22 , wherein the cancer cell is a small-cell lung cancer cell, a non-small-cell lung cancer cell, a sarcoma cell, a pancreatic cancer cell, a breast cancer cell, or a colon cancer cell.
24 . A method of treating cancer, comprising administering the pharmaceutical composition of claim 20 .
25 . The method of claim 24 , wherein the cancer is small-cell lung cancer, non-small-cell lung cancer, sarcoma, pancreatic cancer, breast cancer, or colon cancer.