Method for treating diseases using SMARCA2/4 degraders
The present invention provides a method of treating a disease or disorder with at least one SMARCA2/4 degrader, in a subject who are responders to such treatment based on the presence of tumor specific alterations described therein. The present invention also provides the methods for treating prostate cancer in the subjects who are likely to respond to treatment with SMARCA2/4 degraders.
1. A method of treating a prostate disease in a subject in need thereof comprising:
a) identifying the subject as a responder to treatment with at least one SMARCA2/4 degraders when at least one tumor specific alteration is present in the subject, wherein said tumor specific alteration is:
a mutation, an amplification, or an overexpression of Androgen Receptor (AR) gene;
a loss of function or a deleterious mutation in phosphatase and tensin homolog (PTEN); or
a genomic rearrangement that results in a translocation between a TMPRSS2 gene and an ERG gene; and
the SMARCA2/4 degrader is a compound of formula (I):
or a pharmaceutically acceptable salt thereof or a stereoisomer thereof; wherein,
R 1 is hydrogen, halo, alkyl, alkenyl, alkoxy, hydroxy, hydroxyalkyl, —COOR a —CON(R a ) 2 , or aryl; wherein the aryl is optionally substituted independently with at least one of hydroxy, alkoxy, halo, alkyl, amino, —ONa, —COOR a , or —OCOR a ; wherein R a at each occurrence is hydrogen or alkyl;
R 2 is —NR 3 R 4 or —OR 3 ; wherein, R 3 and R 4 are independently hydrogen or alkyl;
Ring A is a heterocycloalkyl ring or a heteroaryl ring, each optionally substituted independently with at least one of hydroxy, halo or alkyl;
L is a linker with a chemical structure of:
wherein,
the left side of the linker is attached with ring A and the right side of the linker is attached with Targeting Ligand (TL);
R b is hydrogen or alkyl;
R c is alkyl;
n is 0 to 10; and
p is 1 to 5;
Targeting Ligand (TL) is
wherein
R 6 is hydrogen, alkyl, acyl, or haloalkyl;
R 7 is —O—R 5 or halo; wherein R 5 is hydrogen, alkyl, acyl, or Na; and
R 8 is hydrogen or alky; and
b) administering a therapeutically effective amount of at least one SMARCA2/4 degrader to the subject who is identified to respond to the treatment, thereby treating the prostate disease.
2. The method of claim 1 , wherein
the subject is identified as a moderate responder to the treatment with the SMARCA2/4 degraders if one of the tumor specific alterations is present; or
the subject is identified as a high responder to the treatment with the SMARCA2/4 degraders if at least two of the tumor specific alterations are present.
3. The method of claim 1 , wherein the prostate disease is a prostate cancer.
4. The method of claim 3 , wherein the prostate cancer is castration-resistant prostate cancer.
5. The method of claim 1 , wherein the subject has undergone castration or anti-androgen therapy.
6. The method of claim 1 , wherein the SMARCA2/4 degrader is a compound with the chemical structure of:
Compound
No
Structure
1 .
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
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25.
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45.
46.
47
48.
49.
50.
51.
52.
53.
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55.
56.
57. and 58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
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69.
70.
71.
72.
73.
74.
75.
76.
77. and 78.
79.
80.
81.
82.
83. and 84.
85.
86.
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89.
90.
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94.
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96.
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106.
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108.
109.
110.
111.
112.
113.
114.
115.
116.
117.
118.
or a pharmaceutically acceptable salt or a stereoisomer thereof.
7. The method of claim 1 , wherein the step of identifying the subject as a responder with at least one SMARCA2/4 degrader comprises:
a) isolating a biological sample from the subject;
b) determining a presence of at least one tumor specific alteration in the biological sample; and
c) identifying the subject as a responder to said treatment if at least one of the tumor specific alterations is present.
8. The method of claim 1 , wherein administering the at least one SMARCA2/4 degrader inhibits proliferation of prostate cancer cells in the subject.