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  • Alvocidib flavopiridol is a piperidine chromenone http

    2020-06-28

    Alvocidib (flavopiridol) is a piperidine-chromenone derivative (Fig. 6D) that is not FDA approved, but is in clinical trials for breast, endometrial, and several other cancers and hematological malignancies (Table 4) [[100], [101], [102], [103], [104]]. This drug targets CDK9 (IC50 = 3.2 nM) and CDK4 (IC50 = 3.2 nM), it also inhibits other CDKs (CDK1/2/3/6/7), but with IC50 values that are 1–2 orders of magnitude higher. The X-ray crystal structure of alvocidib bound to CDK9 shows that the C4 carbonyl group of the chromenone forms a prostaglandin receptor with the third hinge residue (C106) and the 3-hydroxyl group on the piperidine ring hydrogen bonds with DFG-D167 (Fig. 7E). The drug makes hydrophobic contact with the enzyme including interactions with the β1-strand I25, F30 within the G-rich loop, the β2-strand V33 (CS7), the β3-strand A46 (CS8) and K48 (of the AxK signature), V79 (Sh1) within the αC-β4 loop, the F103 gatekeeper (Sh2), the hinge residues F105, E107, H108, as well as A153 and N154 within the catalytic loop, the β7-strand L156 (CS6), and A166, which occurs prostaglandin receptor just before DFG-D167 of the activation segment (the x of xDFG), and DFG-D167. The drug binds to an active conformation of the CDK9 (αCin, open activation segment, linear R-spine) and is thus a type I inhibitor [53]. Dinaciclib is a pyrazolopyrimidine derivative (Fig. 6E) that is not FDA approved, but is in clinical trials for the treatment of breast and pancreatic cancer and several leukemias (Table 4) [[105], [106], [107], [108], [109], [110], [111]]. This drug targets CDK1/2/5/9 with IC 50 values of 3.2, 1, 1, and 4 nM, respectively. The X-ray crystal structure of the drug bound to the CDK2-cyclin E complex shows that the pyrazolo nitrogen forms a hydrogen bond with the NH group of L83 (the third hinge residue) and the amino group of the drug forms a hydrogen bond with the L83 carbonyl group (Fig. 7F). The drug makes hydrophobic contact with the enzyme including interactions with the β1-strand I10, the β2-strand V18 (CS7), the β3-strand A31, V64 (Sh1) within the αC-β4 loop, the F80 gatekeeper (Sh2), the hinge residues E81, F82, L83, H84, and Q85, Q131 and N132 within the catalytic loop, the β7-strand L134 (CS6), A144, which occurs just before DFG-D145 of the activation segment (the x of xDFG), and DFG-D145. The drug binds to an active conformation of the CDK2-cyclin E complex (αCin, open activation segment, linear R-spine) and is thus a type I inhibitor [53]. The X-ray crystal structure of dinaciclib bound to CDK2 is very similar in terms of hydrogen bonding and hydrophobic interactions. However, the enzyme is in an inactive αCout conformation (Fig. 7G) and consequently the mode of inhibitor binding corresponds to a type I½B inhibitor [53]. Moreover, both structures show that dinaciclib binds within the front pocket and does not extend to the gate area. Roniciclib is an anilino-pyrimidine CDK multikinase inhibitor (Fig. 6I) [112,113] that has been in clinical trials for the treatment of ovarian cancer, small cell lung cancer, and thyroid cancer (Table 4) [114]. The X-ray crystal structure shows that the N1 of the pyrimidine ring hydrogen bonds with the NH group of L83 and the amino group of the drug hydrogen bonds with the carbonyl group of L83, the third hinge residue (Fig. 7H). The sulfonimidoyl oxygen forms a hydrogen bond with the NH group of D86 within the hinge. The drug makes numerous hydrophobic contacts with the enzyme including interactions with the β1-strand I10, the β2-strand V18 (CS7), the β3-strand A31 (CS8), V64 (Sh1) of the back loop, the F80 gatekeeper residue, F82, H84, Q85, D86 of the hinge, the αD-helix K89, the catalytic loop Q131 and N132, A144 (the x residue of xDFG), and DFG-D145. The drug binds to the front pocket and FPI of CDK2. It binds to an inactive αCout/DFG-Din (CODI) conformation is therefore classified as a type I½B inhibitor [53]. It is unclear whether the drug will progress any further in clinical trials.