COMPOUNDS AND USES THEREOF
The present disclosure features compounds useful for the treatment of BAF complex-related disorders.
1 . A method of treating metastatic uveal melanoma in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound having the formula (A):
or a pharmaceutically acceptable salt thereof.
2 . The method of claim 1 , wherein the compound of formula (A) has the structure:
or a pharmaceutically acceptable salt thereof.
3 . The method of claim 2 , wherein the compound of formula (A) has the structure:
or a pharmaceutically acceptable salt thereof.
4 . The method of claim 1 , wherein the compound of formula (A) has the structure:
or a pharmaceutically acceptable salt thereof.
5 . The method of claim 1 , wherein the method comprises administering a pharmaceutical composition comprising the compound of formula (A) having the structure:
or a pharmaceutically acceptable salt thereof,
wherein each substituent D is a position that is deuterium enriched within the pharmaceutical composition.
6 . The method of claim 5 , wherein the pharmaceutical composition comprises the compound of formula (A) having the structure:
or a pharmaceutically acceptable salt thereof,
wherein each substituent D is a position that is deuterium enriched within the pharmaceutical composition.
7 . The method of claim 6 , wherein the pharmaceutical composition comprises the compound of formula (A) having the structure:
or a pharmaceutically acceptable salt thereof,
wherein each substituent D is a position that is deuterium enriched within the pharmaceutical composition.
8 . The method of claim 5 , wherein the pharmaceutical composition comprises the compound of formula (A) having the structure:
or a pharmaceutically acceptable salt thereof,
wherein each substituent D is a position that is deuterium enriched within the pharmaceutical composition.
9 . The method of claim 1 , wherein the metastatic uveal melanoma expresses BRG1 and/or BRM protein.
10 . The method of claim 1 , wherein the subject or metastatic uveal melanoma has an BRG1 loss of function mutation.
11 . The method of claim 10 , wherein the BRG1 loss of function mutation is in the ATPase catalytic domain of the protein.
12 . The method of claim 10 , wherein the BRG1 loss of function mutation is a deletion at the C-terminus of BRG1.
13 . The method of claim 1 , wherein the metastatic uveal melanoma does not have, or has been determined not to have, an epidermal growth factor receptor mutation and/or an anaplastic lymphoma kinase driver mutation.
14 . The method claim 1 , wherein the metastatic uveal melanoma has, or has been determined to have, a KRAS mutation, a mutation in GNAQ, a mutation in GNA11, a mutation in PLCB4, a mutation in CYSLTR2, a mutation in BAP1, a mutation in SF3B1, a mutation in EIF1AX, a TFE3 translocation, a TFEB translocation, a MITF translocation, an EZH2 mutation, a SUZ12 mutation, and/or an EED mutation.
15 . The method of claim 1 , wherein effective amount decreases the activity of a BAF complex in the subject.
16 . The method of claim 1 , wherein the effective amount inhibits BRM and/or BRG1 in the subject.
17 . The method of claim 1 , wherein the effective amount induces apoptosis in the subject.
18 . The method of claim 1 , wherein the metastatic uveal melanoma is resistant to, or failed to respond to, prior treatment with an anticancer therapy.
19 . The method of claim 1 , wherein the method further comprises administering to the subject an anticancer therapy.
20 . The method of claim 19 , wherein the anticancer therapy is surgery, a MEK inhibitor, and/or a PKC inhibitor, or a combination thereof.