CDC7 kinase inhibitors: a survey of recent patent literature (2017-2022).

INTRODUCTION: CDC7 is a serine/threonine kinase which plays an important role in DNA replication. Inhibition of CDC7 in cancer cells causes lethal S phase or M phase progression, whereas inhibition of CDC7 in normal cells does not cause cell death and only leads to cell cycle arrest at the DNA replication checkpoint. Therefore, CDC7 has been recognized as a potential target for novel therapeutic interventions in cancers. AREAS COVERED: Patent literature claiming novel small molecule compounds inhibiting CDC7 disclosed from 2017 to 2022. EXPERT OPINION: Despite the indisputable positive impact of CDC7 as a drug target, there have been reported only a handful of chemical scaffolds as CDC7 inhibitors. Several CDC7 inhibitors have been progressed into clinical trials for cancer treatments, but they did not result in satisfactory efficacies in those trials. One possible reason for the failure might be due to the dose-limiting toxicities, and some of the observed toxicities were thought to be not related to CDC7 inhibition, suggesting it should be important to identify novel chemical scaffolds to eliminate unwanted toxicities. Another important factor is the patient stratification that would enable greater response, and the identification of such predictive biomarkers should be the key to success for the development of CDC7 inhibitors.

Discovery of AS-0141, a Potent and Selective Inhibitor of CDC7 Kinase for the Treatment of Solid Cancers.

CDC7, a serine-threonine kinase, plays conserved and important roles in regulation of DNA replication and has been recognized as a potential anticancer target. We report here the optimization of a series of furanone analogues starting from compound 1 with a focus on ADME properties suitable for clinical development. By replacing the 2-chlorobenzene moiety in 1 with various aliphatic groups, we identified compound 24 as a potent CDC7 inhibitor with excellent kinase selectivity and favorable oral bioavailability in multiple species. Oral administration of 24 demonstrated robust in vivo antitumor efficacy in a colorectal cancer xenograft model. Compound 24 (AS-0141) is currently in phase I clinical trials for the treatment of solid cancers.

Discovery of AS-1763: A Potent, Selective, Noncovalent, and Orally Available Inhibitor of Bruton's Tyrosine Kinase.

Although Bruton's tyrosine kinase (BTK) has been recognized as a validated drug target for the treatment of B-cell malignances, the emergence of clinical resistance to the first-generation covalent BTK inhibitors is becoming a serious concern. As a part of our effort to develop noncovalent BTK inhibitors, a series of novel pyrrolopyrimidines was identified as noncovalent inhibitors of both the wild-type and C481S mutant BTKs. Subsequent lead optimization led to the identification of an orally available, potent, and selective BTK inhibitor 13f (AS-1763) as a next-generation noncovalent BTK inhibitor. With significant efficacies in vivo tumor xenograft models, AS-1763 has advanced to phase 1 clinical trials.

Design and Synthesis of Novel Amino-triazine Analogues as Selective Bruton's Tyrosine Kinase Inhibitors for Treatment of Rheumatoid Arthritis.

Bruton's tyrosine kinase (BTK) is a promising drug target for the treatment of multiple diseases, such as B-cell malignances, asthma, and rheumatoid arthritis. A series of novel aminotriazines were identified as highly selective inhibitors of BTK by a scaffold-hopping approach. Subsequent SAR studies of this series using two conformationally different BTK proteins, an activated form of BTK and an unactivated form of BTK, led to the discovery of a highly selective BTK inhibitor, 4b. With significant efficacy in models in vivo and good ADME and safety profiles, 4b was advanced into preclinical studies.

7-Azaindole: A Versatile Scaffold for Developing Kinase Inhibitors.

The majority of kinase inhibitors have been developed as ATP competitors to interact with a hinge region in ATP binding sites of kinases. 7-Azaindole has been found as an excellent hinge binding motif by making two hydrogen bonds with the kinase hinge region. Vemurafenib, a B-RAF kinase (serine-threonine kinase [STK]) inhibitor approved by the U.S. Food and Drug Administration (FDA) for the treatment of melanoma, was created from this simple 7-azaindole fragment by successful use of structure-based drug design techniques. The huge potential of 7-azaindole as a hinge-binding motif has encouraged many researchers to employ it as a kinase privileged fragment. This paper will review recent examples of 7-azaindole-based kinase inhibitors, and discusses their binding interactions with the kinase hinge regions.

Design and synthesis of novel pyrimidine analogs as highly selective, non-covalent BTK inhibitors.

BTK is a promising target for the treatment of multiple diseases such as B cell malignances, asthma, and rheumatoid arthritis. Here, we report the discovery of a series of novel pyrimidine analogs as potent, highly selective, non-covalent inhibitors of BTK. Compound 25d demonstrated higher affinity to an unactivated conformation of BTK that resulted in an excellent kinase selectivity. Compound 25d showed a good oral bioavailability in mice, and significantly inhibits the PCA reaction in mice.

Discovery of novel furanone derivatives as potent Cdc7 kinase inhibitors.

Cdc7 is a serine-threonine kinase and plays a conserved and important role in DNA replication, and it has been recognized as a potential anticancer target. Herein, we report the design, synthesis and structure-activity relationship of novel furanone derivatives as Cdc7 kinase inhibitors. Compound 13 was identified as a strong inhibitor of Cdc7 with an IC50 value of 0.6 nM in the presence of 1 mM ATP and showed excellent kinase selectivity. In addition, it exhibited slow off-rate characteristics, which may offer advantages over known Cdc7 inhibitors in its potential to yield prolonged inhibitory effects in vivo. Compound 13 potently inhibited Cdc7 activity in cancer cells, and effectively induced cell death.

Design and combinatorial synthesis of a novel kinase-focused library using click chemistry-based fragment assembly.

Fragment-based lead discovery is a new approach for lead generation that has emerged in the past decade. Because the initial fragments identified in the fragment screening typically show weak binding affinity, an intensive medicinal chemistry effort would be required to grow initial fragments into a potential lead compound. Here we demonstrate a kinase focused evolved fragment (KFEF) library, constructed by click chemistry-based fragment assembly, that is a valuable source of kinase inhibitors. This combinatorial assembly of two fragments, kinase-privileged alkyne fragments and diversified azide fragments, by two cycloaddition reactions shows a unique potential for the one-step synthesis of structurally diverse evolved fragments. The screening of this triazole-based KFEF library allowed the rapid identification of potent lead candidates for FLT3 and GSK3ß kinase.

Application of 2-pyridyl-substituted hemithioindigo as a molecular switch in hydrogen-bonded porphyrins.

When the photochromism of 2-(3'-pyridylmethylene)-7-ethylbenzo[b]thiophen-3(2H)-ones (4) was investigated, high thermal stability of the E isomer of 4, 4(E) and good repeatability of the photoinduced E,Z-isomerization were found. Association constants of the 1:1 complexations of 4(Z) and 4(E) with the ureidoporphyrin 1 and with the pentafluorobenzamidoporphyrin 2 were evaluated. We found that 1 captures 4(E) preferentially to 4(Z) and, reversely, 2 prefers 4(Z) to 4(E). On the basis of these differences in the binding ability, we concluded that the repeatable movement of the hemithioindigo, so-called the hemithioindigo shuttle, between two kinds of porphyrins was controlled by the photoirradiation. These movements were applied to create a molecular switch for changes in the quinone distribution between two kinds of porphyrins.

Recognition of a cysteine substrate by E. coli gamma-glutamylcysteine synthetase probed by sulfoximine-based transition-state analogue inhibitors.

A series of sulfoximine-based transition-state analogue inhibitors with a varying alkyl side chain was synthesized to probe the recognition of a Cys substrate by E. coli gamma-glutamylcysteine synthetase (gamma-GCS). The sulfoximines with a small alkyl group (H, methyl, ethyl, propyl, butyl and CH2OH) each served as a slow-binding inhibitor, the sulfoximine with an ethyl being by far the most potent inhibitor to cause facile and irreversible enzyme inhibition. As the size of the side chain changed from an ethyl, the inhibition potency markedly decreased to reduce the overall affinity with concomitant loss in the inactivation rate and with facile enzyme reactivation by dilution. The sulfoximine without a side chain inhibited the enzyme with almost the same potency as that of L-buthionine-(SR)-sulfoximine (BSO). The free energy difference calculated from the inhibition constants indicates that the side chain of Cys was recognized by its size through hydrophobic interaction and contributed almost equally or even more than the carboxy group to the overall binding of Cys in the transition state.