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  • The X ray crystal structure of

    2019-09-10

    The X-ray crystal structure of palbociclib bound to CDK6 without a apexbt calculator (PDB ID: 5L2I) is very similar to that of the CDK6-cyclin V structure (Fig. 7B). However, the drug binds to the αCout conformation of monomeric CDK6 while it binds to the αCin conformation of the CDK6-cyclin V complex. It is likely that the cyclin is responsible for inducing the active-like αCin configuration. The hydrogen bonding pattern is identical as are most of the hydrophobic contacts. Palbociclib makes hydrophobic contacts with the V101 and D102 hinge residues of CDK6, which are lacking in the structure of the CDK6-cyclin V complex. The drug binds within the front pocket and does not extend beyond the gate area (making it a type B inhibitor). Because it binds to an inactive enzyme with DFG-Din and αC-helix out, it is classified as a type I½B inhibitor [53]. As noted above, palbociclib is in clinical trials for diseases other than breast cancer and it is possible that its approval for additional clinical indications may be forthcoming as part of various therapeutic regimens. Ribociclib is an orally effective CDK4/6 inhibitor approved in combination with (i) an aromatase inhibitor for the treatment of pre/perimenopausal or postmenopausal women with HR+/HER2– advanced or metastatic breast cancer, as initial endocrine-based therapy or (ii) fulvestrant for the treatment of postmenopausal women with HR+/HER2– advanced or metastatic breast cancer, as initial endocrine-based therapy or following disease progression on endocrine therapy (Table 4). See Refs. [[90], [91], [92], [93]] for a summary of the clinical trials that led to these approvals. The core scaffold of ribociclib consists of a pyrrolo[2,3d] pyrimidine (Fig. 6B); this drug inhibits CDK4 (IC50 value 10 nM) and CDK6 (39 nM) [94]. The inhibitor potency against CDK1 and CDK2 is much less (>50 μM). The X-ray crystal structure of ribociclib bound to CDK6 shows that the N3 of the pyridine fragment hydrogen bonds with the NH group of V101 (the third hinge residue) and the adjacent amino group NH hydrogen bonds with the V101 carbonyl group (Fig. 7C). The drug carbonyl oxygen hydrogen bonds with the NH group of DFG-D163. Ribociclib makes numerous hydrophobic contacts with the enzyme including interactions with the β1-strand I19, the β2-strand V27 (CS7), the β3-strand A41 (CS8) and K43 (of the AxK signature), V77 (Sh1) within the αC-β4 loop, the F98 gatekeeper (Sh2), the first and second hinge residues (E99, H100), D104 proximal to the αD-helix, T107 of the αD-helix, N150 at the end of the catalytic loop, the β7-strand L152 (CS6), and A162, which occurs just before DFG-D163 of the activation segment (the x of xDFG). Ribociclib is found within the front pocket, the gate area, and FPI. The drug binds to an inactive conformation of the CDK6 (αCout, DFG-Din, and a nonlinear R-spine) and does not extend beyond the gate area and is thus classified as a type I½B inhibitor [53]. Abemaciclib is an orally effective CDK4/6 inhibitor that is FDA approved (i) in combination with an aromatase inhibitor as initial endocrine-based therapy for the treatment of postmenopausal women with HR+/HER2– advanced or metastatic breast cancer (ii) in combination with fulvestrant for the treatment of women with HR+/HER2– advanced or metastatic breast cancer with disease progression following endocrine therapy and (iii) as monotherapy for the treatment of patients with HR+/HER2– advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting. The latter indication is the only CDK inhibitor monotherapy approval. See Refs. [[95], [96], [97], [98]] for a summary of the clinical trials that led to these approvals. The scaffold of abemaciclib consists of a pyridine-pyrimidine-benzimidazole core (Fig. 6C) [99]. The X-ray crystal structure of abemaciclib bound to CDK6 shows that the N1 of the pyrimidine fragment hydrogen bonds with the NH group of V101 (the third hinge residue) and the adjacent amino group NH hydrogen bonds with the V101 carbonyl group (Fig. 7D). The N1 of the benzimidazole of the drug hydrogen bonds with the ε-amino group of the β3-strand K43. Abemaciclib makes numerous hydrophobic contacts with the enzyme including interactions with the β1-strand I19, the β2-strand V27 (CS7), the β3-strand A41 (CS8) and K43 (of the AxK signature), V77 (Sh1) within the αC-β4 loop, the F98 gatekeeper (Sh2), the first and second hinge residues (E99, H100), D104 proximal to the αD-helix, T107 of the αD-helix, the β7-strand L152 (CS6), and A162, which occurs just before DFG-D163 of the activation segment (the x of xDFG). Abemaciclib is found within the front pocket and FPII. The drug binds to an inactive conformation of the CDK6 (αCout, DFG-Din, and a nonlinear R-spine) and does not extend beyond the gate area and is thus classified as a type I½B inhibitor [53].