9csk

From Proteopedia

Crystal structure of CDK4 cyclin D1 in complex with atirmociclib

Structural highlights

9csk is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.253Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

CCND1_HUMAN Note=A chromosomal aberration involving CCND1 may be a cause of B-lymphocytic malignancy, particularly mantle-cell lymphoma (MCL). Translocation t(11;14)(q13;q32) with immunoglobulin gene regions. Activation of CCND1 may be oncogenic by directly altering progression through the cell cycle. Note=A chromosomal aberration involving CCND1 may be a cause of parathyroid adenomas. Translocation t(11;11)(q13;p15) with the parathyroid hormone (PTH) enhancer. Defects in CCND1 are a cause of multiple myeloma (MM) [MIM:254500. MM is a malignant tumor of plasma cells usually arising in the bone marrow and characterized by diffuse involvement of the skeletal system, hyperglobulinemia, Bence-Jones proteinuria and anemia. Complications of multiple myeloma are bone pain, hypercalcemia, renal failure and spinal cord compression. The aberrant antibodies that are produced lead to impaired humoral immunity and patients have a high prevalence of infection. Amyloidosis may develop in some patients. Multiple myeloma is part of a spectrum of diseases ranging from monoclonal gammopathy of unknown significance (MGUS) to plasma cell leukemia. Note=A chromosomal aberration involving CCND1 is found in multiple myeloma. Translocation t(11;14)(q13;q32) with the IgH locus.

Function

CCND1_HUMAN Regulatory component of the cyclin D1-CDK4 (DC) complex that phosphorylates and inhibits members of the retinoblastoma (RB) protein family including RB1 and regulates the cell-cycle during G(1)/S transition. Phosphorylation of RB1 allows dissociation of the transcription factor E2F from the RB/E2F complex and the subsequent transcription of E2F target genes which are responsible for the progression through the G(1) phase. Hypophosphorylates RB1 in early G(1) phase. Cyclin D-CDK4 complexes are major integrators of various mitogenenic and antimitogenic signals. Also substrate for SMAD3, phosphorylating SMAD3 in a cell-cycle-dependent manner and repressing its transcriptional activity. Component of the ternary complex, cyclin D1/CDK4/CDKN1B, required for nuclear translocation and activity of the cyclin D-CDK4 complex.^[1] ^[2]

Publication Abstract from PubMed

CDK4/6 inhibitors have revolutionized treatment of hormone receptor positive (HR+), HER2 non-amplified (HER2-) breast cancer. Yet, all "dual" CDK4/6 inhibitors show common dose-limiting hematologic toxicities, foremost neutropenia. This poses challenges to provide these agents at concentrations necessary to extinguish cell cycling in tumors. HR+ breast cancer cells are highly dependent on CDK4 but not CDK6. By contrast, CDK4 is dispensable for human bone marrow derived cells, due to the primary and compensatory role of CDK6 in hematopoiesis. This prompted us to develop atirmociclib (PF-07220060), a next-generation CDK4 selective inhibitor. Atirmociclib's impact on circulating neutrophils was reduced, in proportion with its increase in CDK4 versus CDK6 selectivity. Realized dose intensification led to greater CDK4 inhibition and deeper anti-tumor responses, pointing to CDK4 target coverage as a limiting factor of CDK4/6 inhibitor efficacy. We also highlight combinatorial agents that may counter acquired resistance to CDK4 selective inhibition and widen its clinical application.

CDK4 selective inhibition improves preclinical anti-tumor efficacy and safety.,Palmer CL, Boras B, Pascual B, Li N, Li D, Garza S, Huser N, Yuan JT, Cianfrogna JA, Sung T, McMillan E, Wei N, Carmody J, Kang AN, Darensburg S, Dodd T, Oakley JV, Solowiej J, Nguyen L, Orr STM, Chen P, Johnson E, Yu X, Diehl WC, Gallego GM, Jalaie M, Ferre RA, Cho-Schultz S, Shen H, Deal JG, Zhang Q, Baffi TR, Xu M, Roh W, Lapira-Miller J, Goudeau J, Yu Y, Gupta R, Kim K, Dann SG, Kan Z, Kath JC, Nair SK, Miller N, Murray BW, Nager AR, Quinlan C, Petroski MD, Zhang C, Sacaan A, VanArsdale T, Anders L Cancer Cell. 2025 Mar 10;43(3):464-481.e14. doi: 10.1016/j.ccell.2025.02.006. PMID:40068598^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ LaBaer J, Garrett MD, Stevenson LF, Slingerland JM, Sandhu C, Chou HS, Fattaey A, Harlow E. New functional activities for the p21 family of CDK inhibitors. Genes Dev. 1997 Apr 1;11(7):847-62. PMID:9106657
↑ Matsuura I, Denissova NG, Wang G, He D, Long J, Liu F. Cyclin-dependent kinases regulate the antiproliferative function of Smads. Nature. 2004 Jul 8;430(6996):226-31. PMID:15241418 doi:10.1038/nature02650
↑ Palmer CL, Boras B, Pascual B, Li N, Li D, Garza S, Huser N, Yuan JT, Cianfrogna JA, Sung T, McMillan E, Wei N, Carmody J, Kang AN, Darensburg S, Dodd T, Oakley JV, Solowiej J, Nguyen L, Orr STM, Chen P, Johnson E, Yu X, Diehl WC, Gallego GM, Jalaie M, Ferre RA, Cho-Schultz S, Shen H, Deal JG, Zhang Q, Baffi TR, Xu M, Roh W, Lapira-Miller J, Goudeau J, Yu Y, Gupta R, Kim K, Dann SG, Kan Z, Kath JC, Nair SK, Miller N, Murray BW, Nager AR, Quinlan C, Petroski MD, Zhang C, Sacaan A, VanArsdale T, Anders L. CDK4 selective inhibition improves preclinical anti-tumor efficacy and safety. Cancer Cell. 2025 Mar 10;43(3):464-481.e14. PMID:40068598 doi:10.1016/j.ccell.2025.02.006