C5-substituted pyrido[2,3-d]pyrimidin-7-ones as highly specific kinase inhibitors targeting the clinical resistance-related EGFR^T790M mutant

Abstract

Development of specific kinase inhibitors has been a long-standing challenge in chemical biology and drug discovery. We have successfully discovered a series of C-5 substituted pyrido[2,3-d]pyrimidin-7-ones as highly specific inhibitors against clinical resistance related EGFR T790M mutant. One of the most promising compounds 9f tightly binds with the EGFR T790M mutant and strongly inhibits its enzymatic function with an IC50 value of 0.80 nM, and displays an extraordinary target specificity with S(35) and S(10) selectivity scores of 0.005 and 0.000, respectively, in a kinase selectivity profiling study against 456 different kinases at 100nM. The compound also selectively suppresses the proliferation of EGFR T790M mutated H1975 NSCLC cells with an IC50 value of 2.80 nM, but is significantly less toxic to cells with wild type EGFR. Compound 9f may serve as a promising lead compound for drug discovery overcoming the acquired resistance of NSCLC patients without adverse toxicities.

Pyrido[2,3-d]pyrimidin-7(8H)-ones: Synthesis and Biomedical Applications

“…On the contrary, in the case of the structures 10 (C5-C6 double bond), 53.53% present only a substituent at C6 (R 5 = H) with the following distribution referring to the total number of structures: 44.46% carbon substituent [55,56] (32.12% phenyl ring [42,57,58]), 4.70% oxygen substituent [59,60], and 1.00% nitrogen substituent [32,61]. In 7.05% of the structures there is a substituent at C5 (R 6 = H) with the following distribution referring to the total number of structures: 4.16% carbon substituent [62,63] (0.10% phenyl ring [16,56]), 0.47% oxygen substituent [56,64], and 2.39% nitrogen substituent [64,65]. There is 7.75% of structures in which R 5 = R 6 = H [66,67].…”

“…These compounds are subsequently converted to the desired 4-unsubstituted compound (55; R 4 = H) upon treatment with a guanidine carbonate 49 under microwave irradiation [99]. We completed our approach to totally dehydrogenated pyrido[2,3d]pyrimidin-7(8H)-ones (56)(57)(58) and (17; R 4 = H) by using several oxidation protocols [16]. The construction of the pyridopyrimidine structure from pyridone 47 usually proceeds with yields higher Only one example of the first kind of disconnection was found in SciFinder, the synthesis of compound 44 [94], an intermediate in the synthesis of pobosaibu, from pyridone 42 upon treatment with S-methylisothiourea (43) and DMF (N,N-Dimethylformamide) which provides the C4 carbon atom (yield not available) ( Figure 17).…”

Synthesis and biological evaluation of novel amino-substituted derivatives of pyrido[2,3-d]pyrimidine as inhibitors of protein kinase CK2

“…The inhibition activity of pyrido [2,3-d]pyrimidine derivatives toward CK2 kinase has not been studied. Noteworthy, the substituted pyrido [2,3-d]pyrimidines are the inhibitors of EGFR [21][22][23][24], Cyclin-Dependent kinases [25,26], Src-tyrosine kinase [27,28] and c-Jun N-Terminal kinase (JNK) [29,30]. It was found that among 2-substituted pyrido [2,3-d]pyrimidin-7-one derivatives there are powerful selective inhibitors of CDK4/6 kinase (Palbociclib) [25], Abl kinase (PD173955) [31,32] and p38 MAP kinase (Pamapimod) [33] which are effective in the treatment of autoimmune and cancer diseases.…”

A convenient approach to the synthesis of new 4-amino substituted derivatives pyrido[2,3-d]pyrimidin-7-one

“…Посилена увага до піридо [2,3-d]піримідин-7-онів зумовлена широким спектром їх біологічної дії. Встановлено, що сполуки даного класу виявляють протипухлинну [1], антипроліферативну [2] та протигерпесну [3] активність, а також є інгібіторами EGFR кінази [4][5][6], циклінзалежної кінази [7,8], Src тирозинкінази [9,10], фосфодіестерази (PDE5) [11] та JNK кінази [12,13]. Серед 2-амінозаміщених похідних піридо [2,3-d]піримідин-7-ону знайдені сильні селективні інгібітори CDK4/6 кінази (Palbociclib) [7], Abl кінази (PD173955) [14,15] та p38 MAP кінази (Pamapimod) [16], які є ефективними для лікування автоімунних та онкологічних хвороб (схема 1).…”