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Article ; Online: Targeting the PI3K/AKT signaling pathway in anticancer research: a recent update on inhibitor design and clinical trials (2020-2023).

Sabbah, Dima A / Hajjo, Rima / Bardaweel, Sanaa K / Zhong, Haizhen A

2024 , Page(s) 1–18

Abstract: Introduction: Recent years have witnessed great achievements in drug design and development targeting the phosphatidylinositol 3-kinase/protein kinase-B (PI3K/AKT) signaling pathway, a pathway central to cell growth and proliferation. The nearest ... ...

Abstract	Introduction: Recent years have witnessed great achievements in drug design and development targeting the phosphatidylinositol 3-kinase/protein kinase-B (PI3K/AKT) signaling pathway, a pathway central to cell growth and proliferation. The nearest neighbor protein-protein interaction networks for PI3K and AKT show the interplays between these target proteins which can be harnessed for drug discovery. In this review, we discuss the drug design and clinical development of inhibitors of PI3K/AKT in the past three years. We review in detail the structures, selectivity, efficacy, and combination therapy of 35 inhibitors targeting these proteins, classified based on the target proteins. Approaches to overcoming drug resistance and to minimizing toxicities are discussed. Future research directions for developing combinational therapy and PROTACs of PI3K and AKT inhibitors are also discussed. Area covered: This review covers clinical trial reports and patent literature on inhibitors of PI3K and AKT published between 2020 and 2023. Expert opinion: To address drug resistance and drug toxicity of inhibitors of PI3K and AKT, it is highly desirable to design and develop subtype-selective PI3K inhibitors or subtype-selective AKT1 inhibitors to minimize toxicity or to develop allosteric drugs that can form covalent bonds. The development of PROTACs of PI3Kα or AKT helps to reduce off-target toxicities.
Language	English
Publishing date	2024-04-09
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1186201-4
ISSN	1744-7674 ; 0962-2594 ; 1354-3776
ISSN (online)	1744-7674
ISSN	0962-2594 ; 1354-3776
DOI	10.1080/13543776.2024.2338100
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Article ; Online: Targeting the EGFR/RAS/RAF signaling pathway in anticancer research: a recent update on inhibitor design and clinical trials (2020-2023).

Hajjo, Rima / Sabbah, Dima A / Bardaweel, Sanaa K / Zhong, Haizhen A

Expert opinion on therapeutic patents

2024 Volume 34, Issue 1-2, Page(s) 51–69

Abstract: Introduction: Recent years have seen significant strides in drug developmenttargeting the EGFR/RAS/RAF signaling pathway which is critical forcell growth and proliferation. Protein-protein interaction networksamong EGFR, RAS, and RAF proteins offer ... ...

Abstract	Introduction: Recent years have seen significant strides in drug developmenttargeting the EGFR/RAS/RAF signaling pathway which is critical forcell growth and proliferation. Protein-protein interaction networksamong EGFR, RAS, and RAF proteins offer insights for drug discovery. This review discusses the drug design and development efforts ofinhibitors targeting these proteins over the past 3 years, detailingtheir structures, selectivity, efficacy, and combination therapy.Strategies to combat drug resistance and minimize toxicities areexplored, along with future research directions. Area covered: This review encompasses clinical trials and patents on EGFR, KRAS,and BRAF inhibitors from 2020 to 2023, including advancements indesign and synthesis of proteolysis targeting chimeras (PROTACs) forprotein degradation. Expert opinion: To tackle drug resistance, designing allosteric fourth-generationEGFR inhibitors is vital. Covalent, allosteric, or combinationaltherapies, along with PROTAC degraders, are key methods to addressresistance and toxicity in KRAS and BRAF inhibitors.
MeSH term(s)	Humans ; Proto-Oncogene Proteins B-raf/metabolism ; Proto-Oncogene Proteins p21(ras) ; Patents as Topic ; Signal Transduction ; ErbB Receptors ; Mutation ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use
Chemical Substances	Proto-Oncogene Proteins B-raf (EC 2.7.11.1) ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2) ; ErbB Receptors (EC 2.7.10.1) ; Protein Kinase Inhibitors ; EGFR protein, human (EC 2.7.10.1)
Language	English
Publishing date	2024-03-12
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1186201-4
ISSN	1744-7674 ; 0962-2594 ; 1354-3776
ISSN (online)	1744-7674
ISSN	0962-2594 ; 1354-3776
DOI	10.1080/13543776.2024.2327307
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Article ; Online: A Critical Assessment of COVID-19 Genomic Vaccines.

Sabbah, Dima A / Hajjo, Rima / Sunoqrot, Suhair

Current topics in medicinal chemistry

2023 Volume 23, Issue 27, Page(s) 2552–2589

Abstract: Vaccines are instrumental tools to fight against novel and re-emerging pathogens and curb pandemics. Vaccination has been an integral part of the multifaceted public health response to the COVID-19 pandemic. Diverse vaccine platforms have been designed ... ...

Abstract	Vaccines are instrumental tools to fight against novel and re-emerging pathogens and curb pandemics. Vaccination has been an integral part of the multifaceted public health response to the COVID-19 pandemic. Diverse vaccine platforms have been designed and are currently at different stages of development. Some vaccines are still in early biological testing, while others have been launched after being approved by regulatory agencies worldwide. Genomic vaccines that deliver parts of the viral DNA or RNA to host cells have gained popularity recently due to their high efficiency and fast manufacture. Furthermore, recent clinical studies encouraged the use of different vaccine platforms within the primary vaccination course to enhance the efficacy of vaccination. Herein, we discuss COVID-19 genomic vaccines, which deliver viral genetic material to host cells through diverse biotechnology platforms, including viral vector vaccines, messenger RNA nucleic acid vaccines, and DNA nucleic acid vaccines. We compare and contrast vaccine characteristics, composition, and pros and cons among different genomic vaccine platforms as well as non-genomic vaccines. This review summarizes all current knowledge about COVID-19 genomic vaccines, which could be highly valuable to researchers interested in public health and vaccine development.
MeSH term(s)	Humans ; COVID-19 Vaccines ; Pandemics/prevention & control ; COVID-19/prevention & control ; Genomics ; Viral Vaccines ; Nucleic Acid-Based Vaccines ; mRNA Vaccines ; Vaccines
Chemical Substances	COVID-19 Vaccines ; Viral Vaccines ; Nucleic Acid-Based Vaccines ; mRNA Vaccines ; Vaccines
Language	English
Publishing date	2023-08-24
Publishing country	United Arab Emirates
Document type	Review ; Journal Article
ZDB-ID	2064823-6
ISSN	1873-4294 ; 1568-0266
ISSN (online)	1873-4294
ISSN	1568-0266
DOI	10.2174/1568026623666230825094341
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Article: Unlocking the Potential of the Human Microbiome for Identifying Disease Diagnostic Biomarkers.

Hajjo, Rima / Sabbah, Dima A / Al Bawab, Abdel Qader

Diagnostics (Basel, Switzerland)

2022 Volume 12, Issue 7

Abstract: The human microbiome encodes more than three million genes, outnumbering human genes by more than 100 times, while microbial cells in the human microbiota outnumber human cells by 10 times. Thus, the human microbiota and related microbiome constitute a ... ...

Abstract	The human microbiome encodes more than three million genes, outnumbering human genes by more than 100 times, while microbial cells in the human microbiota outnumber human cells by 10 times. Thus, the human microbiota and related microbiome constitute a vast source for identifying disease biomarkers and therapeutic drug targets. Herein, we review the evidence backing the exploitation of the human microbiome for identifying diagnostic biomarkers for human disease. We describe the importance of the human microbiome in health and disease and detail the use of the human microbiome and microbiota metabolites as potential diagnostic biomarkers for multiple diseases, including cancer, as well as inflammatory, neurological, and metabolic diseases. Thus, the human microbiota has enormous potential to pave the road for a new era in biomarker research for diagnostic and therapeutic purposes. The scientific community needs to collaborate to overcome current challenges in microbiome research concerning the lack of standardization of research methods and the lack of understanding of causal relationships between microbiota and human disease.
Language	English
Publishing date	2022-07-19
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2662336-5
ISSN	2075-4418
ISSN	2075-4418
DOI	10.3390/diagnostics12071742
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Article: Analyzing the Systems Biology Effects of COVID-19 mRNA Vaccines to Assess Their Safety and Putative Side Effects.

Hajjo, Rima / Sabbah, Dima A / Tropsha, Alexander

Pathogens (Basel, Switzerland)

2022 Volume 11, Issue 7

Abstract: COVID-19 vaccines have been instrumental tools in reducing the impact of SARS-CoV-2 infections around the world by preventing 80% to 90% of hospitalizations and deaths from reinfection, in addition to preventing 40% to 65% of symptomatic illnesses. ... ...

Abstract	COVID-19 vaccines have been instrumental tools in reducing the impact of SARS-CoV-2 infections around the world by preventing 80% to 90% of hospitalizations and deaths from reinfection, in addition to preventing 40% to 65% of symptomatic illnesses. However, the simultaneous large-scale vaccination of the global population will indubitably unveil heterogeneity in immune responses as well as in the propensity to developing post-vaccine adverse events, especially in vulnerable individuals. Herein, we applied a systems biology workflow, integrating vaccine transcriptional signatures with chemogenomics, to study the pharmacological effects of mRNA vaccines. First, we derived transcriptional signatures and predicted their biological effects using pathway enrichment and network approaches. Second, we queried the Connectivity Map (CMap) to prioritize adverse events hypotheses. Finally, we accepted higher-confidence hypotheses that have been predicted by independent approaches. Our results reveal that the mRNA-based BNT162b2 vaccine affects immune response pathways related to interferon and cytokine signaling, which should lead to vaccine success, but may also result in some adverse events. Our results emphasize the effects of BNT162b2 on calcium homeostasis, which could be contributing to some frequently encountered adverse events related to mRNA vaccines. Notably, cardiac side effects were signaled in the CMap query results. In summary, our approach has identified mechanisms underlying both the expected protective effects of vaccination as well as possible post-vaccine adverse effects. Our study illustrates the power of systems biology approaches in improving our understanding of the comprehensive biological response to vaccination against COVID-19.
Language	English
Publishing date	2022-06-29
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2695572-6
ISSN	2076-0817
ISSN	2076-0817
DOI	10.3390/pathogens11070743
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Article ; Online: Analyzing the Systems Biology Effects of COVID-19 mRNA Vaccines to Assess Their Safety and Putative Side Effects

Rima Hajjo / Dima A. Sabbah / Alexander Tropsha

Pathogens, Vol 11, Iss 743, p

2022 Volume 743

Abstract	COVID-19 vaccines have been instrumental tools in reducing the impact of SARS-CoV-2 infections around the world by preventing 80% to 90% of hospitalizations and deaths from reinfection, in addition to preventing 40% to 65% of symptomatic illnesses. However, the simultaneous large-scale vaccination of the global population will indubitably unveil heterogeneity in immune responses as well as in the propensity to developing post-vaccine adverse events, especially in vulnerable individuals. Herein, we applied a systems biology workflow, integrating vaccine transcriptional signatures with chemogenomics, to study the pharmacological effects of mRNA vaccines. First, we derived transcriptional signatures and predicted their biological effects using pathway enrichment and network approaches. Second, we queried the Connectivity Map (CMap) to prioritize adverse events hypotheses. Finally, we accepted higher-confidence hypotheses that have been predicted by independent approaches. Our results reveal that the mRNA-based BNT162b2 vaccine affects immune response pathways related to interferon and cytokine signaling, which should lead to vaccine success, but may also result in some adverse events. Our results emphasize the effects of BNT162b2 on calcium homeostasis, which could be contributing to some frequently encountered adverse events related to mRNA vaccines. Notably, cardiac side effects were signaled in the CMap query results. In summary, our approach has identified mechanisms underlying both the expected protective effects of vaccination as well as possible post-vaccine adverse effects. Our study illustrates the power of systems biology approaches in improving our understanding of the comprehensive biological response to vaccination against COVID-19.
Keywords	COVID-19 ; mRNA vaccine ; informatics workflow ; SARS-CoV-2 ; systems biology ; vaccine adverse events ; Medicine ; R
Language	English
Publishing date	2022-06-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Synthesis, Molecular Modeling and Biological Evaluation of Novel Trifluoromethyl Benzamides as Promising CETP Inhibitors.

Abu Khalaf, Reema / Abusaad, Amani / Al-Nawaiseh, Bara'a / Sabbah, Dima / Albadawi, Ghadeer

Current computer-aided drug design

2023

Abstract: Background: Hyperlipidemia is considered a major risk factor for the progress of atherosclerosis.: Objective: Cholesteryl ester transfer protein (CETP) facilitates the relocation of cholesterol esters from HDL to LDL. CETP inhibition produces higher ... ...

Abstract	Background: Hyperlipidemia is considered a major risk factor for the progress of atherosclerosis. Objective: Cholesteryl ester transfer protein (CETP) facilitates the relocation of cholesterol esters from HDL to LDL. CETP inhibition produces higher HDL and lower LDL levels. Methods: Synthesis of nine benzylamino benzamides 8a-8f and 9a-9c was performed. Results: In vitro biological study displayed potential CETP inhibitory activity, where compound 9c had the best activity with an IC50 of 1.03 µM. Induced-fit docking demonstrated that 8a-8f and 9a-9c accommodated the CETP active site and hydrophobic interaction predominated ligand/ CETP complex formation. Conclusion: Pharmacophore mapping showed that this scaffold endorsed CETP inhibitors features and consequently elaborated the high CETP binding affinity.
Language	English
Publishing date	2023-05-09
Publishing country	United Arab Emirates
Document type	Journal Article
ISSN	1875-6697
ISSN (online)	1875-6697
DOI	10.2174/1573409919666230509123852
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Article: A cross-sectional study confirms temporary post-COVID-19 vaccine menstrual irregularity and the associated physiological changes among vaccinated women in Jordan.

Almomani, Ensaf Y / Hajjo, Rima / Qablan, Ahmad / Sabbah, Dima A / Al-Momany, Abass

Frontiers in medicine

2023 Volume 10, Page(s) 1211283

Abstract: Background: COVID-19 vaccines continue to save people's lives around the world; however, some vaccine adverse events have been a major concern which slowed down vaccination campaigns. Anecdotal evidence pointed to the vaccine effect on menstruation but ... ...

Abstract	Background: COVID-19 vaccines continue to save people's lives around the world; however, some vaccine adverse events have been a major concern which slowed down vaccination campaigns. Anecdotal evidence pointed to the vaccine effect on menstruation but evidence from the adverse event reporting systems and the biomedical literature was lacking. This study aimed to investigate the physiological changes in women during menstruation amid the COVID-19 vaccination. Methods: A cross-sectional online survey was distributed to COVID-19 vaccinated women from Nov 2021 to Jan 2022. The results were analyzed using the SPSS software. Results: Among the 564 vaccinated women, 52% experienced significant menstrual irregularities post-vaccination compared to before regardless of the vaccine type. The kind of menstrual irregularity varied among the vaccinated women, for example, 33% had earlier menstruation, while 35% reported delayed menstruation. About 31% experienced heavier menstruation, whereas 24% had lighter menstrual flow. About 29% had menstruation last longer, but 13% had it shorter than usual. Noteworthy, the menstrual irregularities were more frequent after the second vaccine shot, and they disappeared within 3 months on average. Interestingly, 24% of the vaccinated women reported these irregularities to their gynecologist. Conclusion: The COVID-19 vaccine may cause physiological disturbances during menstruation. Luckily, these irregularities were short-termed and should not be a reason for vaccine hesitancy in women. Further studies are encouraged to unravel the COVID-19 vaccine adverse effect on women's health.
Language	English
Publishing date	2023-10-06
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2775999-4
ISSN	2296-858X
ISSN	2296-858X
DOI	10.3389/fmed.2023.1211283
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Article ; Online: Identifying a causal link between prolactin signaling pathways and COVID-19 vaccine-induced menstrual changes.

Hajjo, Rima / Momani, Ensaf / Sabbah, Dima A / Baker, Nancy / Tropsha, Alexander

NPJ vaccines

2023 Volume 8, Issue 1, Page(s) 129

Abstract: COVID-19 vaccines have been instrumental tools in the fight against SARS-CoV-2 helping to reduce disease severity and mortality. At the same time, just like any other therapeutic, COVID-19 vaccines were associated with adverse events. Women have reported ...

Abstract	COVID-19 vaccines have been instrumental tools in the fight against SARS-CoV-2 helping to reduce disease severity and mortality. At the same time, just like any other therapeutic, COVID-19 vaccines were associated with adverse events. Women have reported menstrual cycle irregularity after receiving COVID-19 vaccines, and this led to renewed fears concerning COVID-19 vaccines and their effects on fertility. Herein we devised an informatics workflow to explore the causal drivers of menstrual cycle irregularity in response to vaccination with mRNA COVID-19 vaccine BNT162b2. Our methods relied on gene expression analysis in response to vaccination, followed by network biology analysis to derive testable hypotheses regarding the causal links between BNT162b2 and menstrual cycle irregularity. Five high-confidence transcription factors were identified as causal drivers of BNT162b2-induced menstrual irregularity, namely: IRF1, STAT1, RelA (p65 NF-kB subunit), STAT2 and IRF3. Furthermore, some biomarkers of menstrual irregularity, including TNF, IL6R, IL6ST, LIF, BIRC3, FGF2, ARHGDIB, RPS3, RHOU, MIF, were identified as topological genes and predicted as causal drivers of menstrual irregularity. Our network-based mechanism reconstruction results indicated that BNT162b2 exerted biological effects similar to those resulting from prolactin signaling. However, these effects were short-lived and didn't raise concerns about long-term infertility issues. This approach can be applied to interrogate the functional links between drugs/vaccines and other side effects.
Language	English
Publishing date	2023-09-01
Publishing country	England
Document type	Journal Article
ISSN	2059-0105
ISSN (online)	2059-0105
DOI	10.1038/s41541-023-00719-6
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Article ; Online: Targeting Human Proteins for Antiviral Drug Discovery and Repurposing Efforts: A Focus on Protein Kinases.

Hajjo, Rima / Sabbah, Dima A / Abusara, Osama H / Kharmah, Reham / Bardaweel, Sanaa

Viruses

2023 Volume 15, Issue 2

Abstract: Despite the great technological and medical advances in fighting viral diseases, new therapies for most of them are still lacking, and existing antivirals suffer from major limitations regarding drug resistance and a limited spectrum of activity. In fact, ...

Abstract	Despite the great technological and medical advances in fighting viral diseases, new therapies for most of them are still lacking, and existing antivirals suffer from major limitations regarding drug resistance and a limited spectrum of activity. In fact, most approved antivirals are directly acting antiviral (DAA) drugs, which interfere with viral proteins and confer great selectivity towards their viral targets but suffer from resistance and limited spectrum. Nowadays, host-targeted antivirals (HTAs) are on the rise, in the drug discovery and development pipelines, in academia and in the pharmaceutical industry. These drugs target host proteins involved in the virus life cycle and are considered promising alternatives to DAAs due to their broader spectrum and lower potential for resistance. Herein, we discuss an important class of HTAs that modulate signal transduction pathways by targeting host kinases. Kinases are considered key enzymes that control virus-host interactions. We also provide a synopsis of the antiviral drug discovery and development pipeline detailing antiviral kinase targets, drug types, therapeutic classes for repurposed drugs, and top developing organizations. Furthermore, we detail the drug design and repurposing considerations, as well as the limitations and challenges, for kinase-targeted antivirals, including the choice of the binding sites, physicochemical properties, and drug combinations.
MeSH term(s)	Humans ; Protein Kinases ; Antiviral Agents/pharmacology ; Drug Repositioning ; Drug Discovery ; Drug Design
Chemical Substances	Protein Kinases (EC 2.7.-) ; Antiviral Agents
Language	English
Publishing date	2023-02-19
Publishing country	Switzerland
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v15020568
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