Rational Design, Synthesis and Biological Evaluation of Pyrimidine-4,6-diamine derivatives as Type-II inhibitors of FLT3 Selective Against c-KIT.

FMS-like Tyrosine Kinase 3 (FLT3) is a clinically validated target for acute myeloid leukemia (AML). Inhibitors targeting FLT3 have been evaluated in clinical studies and have exhibited potential to treat FLT3-driven AML. A frequent, clinical limitation is FLT3 selectivity, as concomitant inhibition of FLT3 and c-KIT is thought to cause dose-limiting myelosuppression. Through a rational design approach, novel FLT3 inhibitors were synthesized employing a pyridine/pyrimidine warhead. The most potent compound identified from the studies is compound 13a, which exhibited an IC50 value of 13.9 ± 6.5 nM against the FLT3 kinase with high selectivity over c-KIT. Mechanism of action studies suggested that 13a is a Type-II kinase inhibitor, which was also supported through computer aided drug discovery (CADD) efforts. Cell-based assays identified that 13a was potent on a variety of FLT3-driven cell lines with clinical relevance. We report herein the discovery and therapeutic evaluation of 4,6-diamino pyrimidine-based Type-II FLT3 inhibitors, which can serve as a FLT3-selective scaffold for further clinical development

AI-enabled remote monitoring of vital signs for COVID-19: methods, prospects and challenges

The COVID-19 pandemic has overwhelmed the existing healthcare infrastructure in many parts of the world. Healthcare professionals are not only over-burdened but also at a high risk of nosocomial transmission from COVID-19 patients. Screening and monitoring the health of a large number of susceptible or infected individuals is a challenging task. Although professional medical attention and hospitalization are necessary for high-risk COVID-19 patients, home isolation is an effective strategy for low and medium risk patients as well as for those who are at risk of infection and have been quarantined. However, this necessitates effective techniques for remotely monitoring the patients’ symptoms. Recent advances in Machine Learning (ML) and Deep Learning (DL) have strengthened the power of imaging techniques and can be used to remotely perform several tasks that previously required the physical presence of a medical professional. In this work, we study the prospects of vital signs monitoring for COVID-19 infected as well as quarantined individuals by using DL and image/signal-processing techniques, many of which can be deployed using simple cameras and sensors available on a smartphone or a personal computer, without the need of specialized equipment. We demonstrate the potential of ML-enabled workflows for several vital signs such as heart and respiratory rates, cough, blood pressure, and oxygen saturation. We also discuss the challenges involved in implementing ML-enabled techniques

Insights into Current Tropomyosin Receptor Kinase (TRK) inhibitors: development and clinical application

The use of kinase-directed precision medicine has been heavily pursued since the discovery and development of imatinib. Annually, it is estimated that around ∼20 000 new cases of tropomyosin receptor kinase (TRK) cancers are diagnosed, with the majority of cases exhibiting a TRK genomic rearrangement. In this Perspective, we discuss current development and clinical applications for TRK precision medicine by providing the following: (1) the biological background and significance of the TRK kinase family, (2) a compilation of known TRK inhibitors and analysis of their cocrystal structures, (3) an overview of TRK clinical trials, and (4) future perspectives for drug discovery and development of TRK inhibitors

Targeting Aurora Kinase B for Cancer Therapy: Molecular Dynamics Studies and Discovery of Selective First-in-Class Inhibitors

Treating cancers has been one of the greatest challenges of biomedical research in the last few decades. However, the advent of targeted therapy has revolutionized the treatment options for cancer patients. Unlike traditional chemotherapy which are indiscriminately cytotoxic, targeted therapeutics agents are directed towards specific proteins or genes which are crucial for a particular cancer. Kinases, due to their extensive role in several biological processes including cell division, growth, proliferation, angiogenesis, and apoptosis, are often the appropriate ‘targets’ for targeted therapy. Thus, kinase inhibitors have been one of the most widely studied drug classes for cancer therapy, with 61 kinase inhibitors approved by FDA till date. Although several kinases are widely studied for their role in cancers and explored for therapeutic potential, there is immense room for progress. Firstly, an inhibitor for several of these kinases is yet to be approved for clinical use. Secondly, kinase inhibitors are of various classes, and for many kinases, although inhibitor of a particular class is known, inhibitors of other classes, which could offer clinical benefit, are yet to be discovered. Thirdly, combining targeted therapies with other therapies has shown great promise. Many of these combinations involving kinase inhibitors are yet to be explored. The work presented in this thesis is directed mainly towards Aurora Kinase B. Drug discovery projects in the last 2 decades targeting Aurora Kinase B resulted in several Aurora B inhibitors. However, none of them are approved for clinical use. Currently, drug discovery and development efforts targeting Aurora B face the following challenges: (1) all the known Aurora B inhibitors are ATP-competitive which bind to the active state of the kinase. There are no inhibitors which are non-ATP-competitive (2) structure-based drug design and discovery of non-ATP-competitive inhibitors needs structural knowledge of the inactive state of Aurora B which is not yet crystallized (3) most of the Aurora B inhibitors evaluated in clinical trials are associated with the side-effect febrile neutropenia. Although this could be a direct result of inhibition of Aurora Kinases which are involved in mitosis, most of these drugs also inhibit Class III receptor tyrosine kinases, particularly FLT3 and KIT, which are important for normal hematopoiesis. This work is aimed at addressing these challenges. Since the inactive state of Aurora B is not experimentally determined, we employed computational methods to simulate the inactive conformation from the experimentally determined active conformation. The important structural features during the flip were characterized and the potentially druggable intermediate conformations identified. Also, the interactions and other requirements important for anchoring Aurora B in a particular conformation were identified. Based on this knowledge, a series of Aurora B inhibitors were designed. Following a cycle of synthesis and enzymatic screening, the structure activity relationship (SAR) was established and the scaffold optimized for Aurora B inhibition. The enzyme kinetics revealed that the lead compound SP-96 shows non-ATP-competitive inhibition, which makes it a first-in-class inhibitor. Also, SP-96 shows > 1200-fold selectivity against FLT3 and KIT, which promises a better side-effect profile. The pharmacophore features responsible for this selectivity was also established. Further, NCI60 data of SP-96 shows that growth inhibition effects of the molecule in certain triple negative breast cancer cell lines, for which targeted therapy is yet to be discovered. Knowledge of the pharmacophore features responsible for selectivity against tyrosine kinases, mixed with the concept of bioisosterism, was used to explore the activity of pyrrolo[2,3-d]pyrimidine scaffold in tyrosine kinases. After a typical medicinal chemistry cycle of synthesis and screening, a lead compound with activity against RET-wt, RET V804M mutant and RET fusion driven cell line was identified. In total, the thesis presented herein seeks to fill some of the gaps existing in kinase drug discovery, particularly Aurora Kinase B, with the ultimate aim of improved treatment options for the increasing number of cancer patients in the world

A Review on the Role of Machine Learning in Enabling IoT Based Healthcare Applications

10.1109/access.2021.3059858IEEE Access938859-3889

Rational Design, Synthesis and Biological Evaluation of Pyrimidine-4,6-diamine derivatives as Type-II inhibitors of FLT3 Selective Against c-KIT.

FMS-like Tyrosine Kinase 3 (FLT3) is a clinically validated target for acute myeloid leukemia (AML). Inhibitors targeting FLT3 have been evaluated in clinical studies and have exhibited potential to treat FLT3-driven AML. A frequent, clinical limitation is FLT3 selectivity, as concomitant inhibition of FLT3 and c-KIT is thought to cause dose-limiting myelosuppression. Through a rational design approach, novel FLT3 inhibitors were synthesized employing a pyridine/pyrimidine warhead. The most potent compound identified from the studies is compound 13a, which exhibited an IC50 value of 13.9 ± 6.5 nM against the FLT3 kinase with high selectivity over c-KIT. Mechanism of action studies suggested that 13a is a Type-II kinase inhibitor, which was also supported through computer aided drug discovery (CADD) efforts. Cell-based assays identified that 13a was potent on a variety of FLT3-driven cell lines with clinical relevance. We report herein the discovery and therapeutic evaluation of 4,6-diamino pyrimidine-based Type-II FLT3 inhibitors, which can serve as a FLT3-selective scaffold for further clinical development

Discovery of N-trisubstituted Pyrimidine Derivatives as Type-I RET and RET Gatekeeper Mutant Inhibitors with a Novel Kinase Binding Pose

Rearranged during transfection (RET) kinase is an attractive therapeutic target in cancers in which RET gene fusions and point mutations in the kinase domain are reported. Mutation of V804, the RET gatekeeper residue, leads to resistance to several FDA approved inhibitors. In this study, we discovered a series of N-trisubstituted pyrimidine derivatives as potent inhibitors for both wt-RET and RETV804M. Enzyme kinetics indicate that these inhibitors are ATP-competitive. The X-ray structure of a representative inhibitor in complex with RET reveals that the compound binds a unique pose that bifurcates beneath the P-loop; this is the first time that such a binding pose for a kinase inhibitor is described. Moreover, this binding pose explained the ability of N-trisubstituted pyrimidine compounds of targeting RETV804M. A structure activity relationship (SAR) was performed and compound 20 was identified as a lead one, displaying potent inhibition of RET and RETV804M with IC50 of 6.20nM and 18.68nM, respectively. Additionally, compound 20 showed potent anti-proliferative activity in CCDC6-RET driven LC-2/ad lung carcinoma cells. A wound healing assay indicated that compound 20 inhibits migration of RET mutant tumor cells. Analysis of apoptosis and RET phosphorylation indicated that such biological activities were mediated by RET inhibition. Collectively, N-trisubstituted pyrimidine derivatives could serve as scaffolds for the discovery and development of potent type-I RET and its gatekeeper mutant inhibitors for the treatment of RET driven cancers