Compositions and methods for treating cdk4/6-mediated cancer
AssigneeIcahn School of Medicine at Mount Sinai
InventorsJian Jin, Xiaobao Yang, Jing Liu, Yan Xiong, Poulikos Poulikakos, Zoi Karoulia, Xuewei Wu, Tamer Ahmed
Life of this patent
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Abstract
Methods for designing heterobifunctional small molecules which selectively degrade/disrupt CDK4/6 and compositions and methods of using such degraders/disruptors to treat CDK4/6-mediated cancer are provided.
Claims40
A bivalent compound comprising a cyclin-dependent kinase 4/6 (CDK4/6) ligand conjugated to a degradation/disruption tag.
A bivalent compound selected from the group consisting of XY028-082, XY028-003, XY028-004, XY028-005, XY019-098, XY028-006, XY028-007, XY028-008, XY028-009, XY028-085, XY028-084, XY028-083, XY028-132, XY028-133, XY019-106, XY028-162, XY028-163, XY028-002, XY028-114, XY028-097, XY019-108, XY028-105, XY028-106, XY028-140, XY028-141, XY028-142, XY028-143, XY028-144, XY028-145, YX26-56, YX26-66, YX26-58, YX30-108, YX30-107, YX30-85, YX30-86, YX30-117, YX30-118, YX30-126, YX30-125, XY028-186, YX33-29, YX33-31, YX33-74, YX33-94, YX33-108, YX33-96, YX33-97, YX33-109, YX33-110, YX33-112, YX33-123, YX35-48, YX39-47, YX39-48, YX39-56, YX39-65, YX39-74, YX39-123, YX39-124, YX39-147, YX44-18, YX44-19, YX44-22, YX44-46, YX44-48, YX44-78, YS36-95, YS36-60, YS36-61, YS36-62, YS36-63, YS36-64, YS36-65, YS36-66, YS36-67, YS36-68, YS36-69, YS36-70, YS36-71, compound examples 80-135, and analogs thereof.
A method of treating a cyclin-dependent kinase 4/6 (CDK4/6)-mediated cancer, which comprises administering to a subject in need thereof with a CDK4/6-mediated cancer a bivalent compound comprising a CDK4/6 ligand conjugated to a degradation/disruption tag.
A method for identifying a bivalent compound which mediates degradation/disruption of CDK4 or CDK6, the method comprising:
- providing a heterobifunctional test compound comprising a CDK4/6 ligand conjugated to a degradation/disruption tag;
- contacting the heterobifunctional test compound with a cell comprising a ubiquitin ligase and at least one of CDK4 and CDK6;
- determining whether CDK4 or CDK6 levels decrease in the cell;
- and
- (i) identifying the heterobifunctional test compound as a bivalent compound which mediates degradation/reduction of CDK4 if CDK4 levels decrease in the cell and CDK6 levels do not decrease in the cell,
- (ii) identifying the heterobifunctional test compound as a bivalent compound which mediates degradation/reduction of CDK6 if CDK6 levels decrease in the cell and CDK4 levels do not decrease in the cell, or
- (iii) identifying the heterobifunctional test compound as a bivalent compound which mediates degradation/reduction of CDK4 and CDK6 if both CDK4 and CDK6 levels decrease in the cell.
Dependencies are inferred from the claim text.