The investigators used co-immunoprecipitation assays to identify BRD4 as an FBXO28-associated protein, then examined how the two molecules regulate transcription. FBXO28 mediated ubiquitination of BRD4 at lysine 395 through a lysine 63-linked conjugation model. Unlike ubiquitination processes that direct a substrate for destruction, this modification did not cause BRD4 degradation. Instead, it enhanced BRD4 activity as a transcriptional coactivator: changing FBXO28 expression altered the abundance of BRD4-target genes and affected BRD4 binding to the promoters of those genes.

The proposed downstream mechanism involves P-TEFb, a complex associated with transcriptional elongation. FBXO28-dependent ubiquitination of BRD4 facilitated activation of P-TEFb and subsequent phosphorylation of the serine 2 residue in the C-terminal domain of the largest subunit of RNA polymerase II. This phosphorylation was linked by the researchers to the initiation of transcription. The study therefore connects a ubiquitin-signaling event to changes in transcriptional programs that support the proliferation and movement of lung cancer cells.

The authors also described a positive feedback loop. BRD4 bound to the FBXO28 promoter, and increased FBXO28 transcription further strengthened the relationship between the two proteins. The experimentally supported model is that FBXO28 ubiquitinates BRD4, activated BRD4 increases FBXO28 expression, and elevated FBXO28 can reinforce BRD4 modification and activity. Overall, the work implicates the FBXO28–BRD4 feedback loop as a contributor to non-small cell lung cancer malignancy. Because the evidence comes from patient-sample associations and functional cellular experiments, the results indicate a promising research pathway rather than demonstrating an effective intervention or clinical benefit in people with lung cancer.

Subject of Research: FBXO28-mediated BRD4 ubiquitination and transcriptional activation in non-small cell lung cancer.

Article Title: FBXO28 promotes the malignancy of non-small cell lung cancer through ubiquitination-mediated activation of BRD4

Article References: Liang, Y., Jiao, Q., Zhang, F., Bai, W., Yang, J., Luo, X., Zhang, J., Tang, X., Tang, J., Zhang, Z., Yan, J., Lai, F., Sun, L., Cao, L., Zhang, W., & Lv, X.-B. (2026). FBXO28 promotes the malignancy of non-small cell lung cancer through ubiquitination-mediated activation of BRD4. Cell Death Discovery. https://doi.org/10.1038/s41420-026-03364-9

Image Credits: AI Generated

DOI: 10.1038/s41420-026-03364-9

Keywords: FBXO28, BRD4, non-small cell lung cancer, ubiquitination, transcription, P-TEFb, RNA polymerase II, cancer progression, positive feedback loop, promotes, malignancy, non-small

Bromodomain proteins are epigenetic readers. They do not chemically modify chromatin themselves; instead, they recognize acetylated lysine residues on histone tails and on certain non-histone proteins, and recruit transcriptional regulators and chromatin-remodeling complexes to those acetylated regions. The human genome encodes 61 bromodomains distributed across 46 proteins, organized into eight major evolutionary families. All bromodomains share a conserved four-helix fold, with the ZA and BC loops forming a hydrophobic pocket that binds acetyl-lysine through a conserved asparagine residue. Variation in these loops determines which acetylation patterns each bromodomain recognizes, and this structural diversity underlies the remarkable functional specialization within the family, from transcriptional activation and enhancer regulation to DNA repair and innate immune signaling.

The most intensively studied bromodomain proteins in virology belong to the bromodomain and extra-terminal (BET) family: BRD2, BRD3, BRD4, and BRDT. These proteins carry two tandem bromodomains and an extra-terminal domain, and BRD4 and BRDT additionally possess a C-terminal domain that interacts with positive transcription elongation factor b (P-TEFb), a complex of CDK9 and Cyclin T1 that drives RNA polymerase II-dependent transcriptional elongation. Because integrated retroviruses depend entirely on host transcription machinery, BET proteins sit at the heart of how HIV-1 and HTLV-1 control expression of their genomes. Non-BET bromodomain proteins, by contrast, often operate within ATP-dependent SWI/SNF chromatin-remodeling complexes, where they regulate chromatin accessibility rather than elongation directly.

In HIV-1 infection, the role of BRD4 has been defined over two decades of work. Early studies identified BRD4 as a recruiter of P-TEFb to cellular promoters, and subsequent research revealed a more nuanced picture: BRD4 can act as a negative regulator of HIV transcription by competing with the viral Tat protein for access to P-TEFb. A conserved P-TEFb-binding domain within BRD4 inhibits HIV transcription, and related work showed that BRD4 modulates Tat-dependent elongation through phosphorylation of CDK9 at threonine 29. Later studies demonstrated that BRD4 liberates P-TEFb from the inhibitory 7SK snRNP complex through a dual-binding mechanism, and that BRD4 is also an atypical kinase capable of phosphorylating serine 2 of the RNA polymerase II C-terminal domain. Together these findings established the Tat–P-TEFb axis, and BRD4’s position within it, as a central determinant of HIV-1 gene expression.

Bromodomain proteins also govern HIV latency, the state in which proviral DNA sits transcriptionally silent in host chromatin, forming the reservoir that prevents eradication of the virus. BET inhibition with compounds such as JQ1 reactivates latent HIV-1, both by antagonizing BRD4-mediated repression of Tat transactivation and through Tat-independent mechanisms. Notably, the short isoform of BRD4 was shown to promote latency by recruiting repressive SWI/SNF complexes to the proviral promoter, a finding that directly connected bromodomain biology to chromatin-remodeling machinery. Genome-wide CRISPR screens have since confirmed that latency is maintained by interconnected epigenetic and transcriptional pathways rather than by any single host factor. Therapeutically, BET inhibitors have been explored both as latency-reversing agents for shock-and-kill strategies and, in the case of BRD4-selective molecules such as ZL0580, as block-and-lock compounds that durably suppress proviral transcription.

Against this backdrop, BRD9 has recently entered the field. BRD9 is not a BET protein; it contains a single bromodomain with a distinctive tyrosine gatekeeper residue and serves as a defining component of the non-canonical BAF (ncBAF) complex, one of three compositionally distinct mammalian SWI/SNF assemblies alongside canonical BAF and PBAF. ncBAF contains BRD9 together with GLTSCR1 or GLTSCR1L, and its ATP-dependent remodeling activity alters nucleosome positioning and the accessibility of regulatory DNA. In 2025, Luk and colleagues provided the first direct experimental evidence that BRD9-containing ncBAF complexes regulate chromatin accessibility at the HIV-1 provirus, influencing proviral transcriptional competence, latency maintenance, and viral reactivation. Using complementary genetic and pharmacological approaches, the study established BRD9 as a bona fide host factor involved in HIV persistence, and suggested that selective BRD9 inhibition could support block-and-lock strategies aimed at durable proviral silencing.

The review’s authors are careful to stress that this single study marks the beginning, not the culmination, of BRD9 research in retrovirology. Independent validation, mechanistic work across multiple reservoir cell types, and characterization of BRD9 interaction partners remain necessary. Several fundamental questions are unresolved: how BRD9 is recruited to retroviral chromatin, whether it cooperates with or acts independently of BRD4, and what its genomic occupancy at proviral loci looks like. The authors also caution that most bromodomain-targeted compounds evaluated in HIV cure research, including JQ1, CPI-203, and OTX015, are pan-BET inhibitors, so their antiviral effects cannot be attributed to BRD9. Future studies will require selective BRD9 inhibitors or degraders to distinguish BRD9-specific mechanisms from the broader consequences of BET inhibition.

The picture for HTLV-1 is even more preliminary. No direct experimental study has yet examined BRD9 in HTLV-1 infection. What is established comes almost entirely from BET protein research. The viral transactivator Tax was shown to modulate the BRD4–P-TEFb interaction, competing with BRD4 and with the inhibitory 7SK snRNP/HEXIM1 complex to increase the pool of active P-TEFb available for the HTLV-1 long terminal repeat promoter. BET inhibition with JQ1 suppresses Tax-mediated cellular transformation and reduces NF-κB signaling, a pathway constitutively activated in HTLV-1-transformed cells. More recently, BET inhibition disrupted the BATF3/IRF4-dependent transcriptional network essential for adult T-cell leukemia/lymphoma (ATLL) cell survival, supporting the idea that ATLL cells are transcriptionally addicted to bromodomain-regulated programs. Resistance, however, is a documented challenge: loss of FBXW7-mediated BRAF degradation promotes BET inhibitor resistance in ATLL cells through sustained MAPK signaling, underscoring the likely need for combination therapies.

Whether BRD9 contributes to HTLV-1 transcription, proviral chromatin organization, Tax- or HBZ-mediated regulation, or ATLL leukemogenesis remains entirely unknown, and the review presents it only as a biologically plausible, untested candidate. Given ncBAF’s roles in enhancer accessibility, three-dimensional chromatin architecture, and signaling-dependent transcription, the question is well worth asking. The authors propose a research agenda: mapping BRD9 genomic occupancy with ChIP-seq, CUT&RUN, CUT&Tag, and single-cell multi-omics; identifying viral and cellular interaction partners proteomically; testing BRD9 function across HIV reservoirs including resting CD4-positive T cells, macrophages, and tissue-resident immune cells; and evaluating selective BRD9 inhibitors, degraders, and PROTACs in preclinical retroviral models. If BRD9-specific modulation proves feasible and safe, it could open a genuinely new epigenetic front in the effort to control retroviral persistence, reverse latency, or prevent retrovirus-associated malignancy, while reinforcing a broader lesson of the field: bromodomain proteins are not a single mechanistic class, but a diverse family of chromatin readers whose individual contributions to viral pathogenesis must each be established on their own experimental footing.

Subject of Research: The roles of bromodomain-containing proteins, particularly BRD9 and BRD4, in regulating chromatin, transcription, and latency during HIV-1 and HTLV-1 infection

Article Title: BRD proteins in human retroviral infection: emerging evidence from HIV-1 and future perspectives for HTLV-1

Article References: Akbarin, M. M., Farjami, Z., & Álvarez, H. R. (2026). BRD proteins in human retroviral infection: emerging evidence from HIV-1 and future perspectives for HTLV-1. Molecular Biology Reports, 53(1), Article 1603. https://doi.org/10.1007/s11033-026-12778-8

Image Credits: AI Generated

DOI: 10.1007/s11033-026-12778-8

Keywords: BRD9, BRD4, bromodomain proteins, HIV-1, HTLV-1, viral latency, chromatin remodeling, ncBAF, P-TEFb, epigenetics, ATLL, retrovirus

The central premise of the review is that HPV-mediated checkpoint disruption is only the first act. Once the p53 and RB brakes are released, the malignant cell must still stabilize a proliferative, treatment-tolerant state, and the authors propose that this stabilization depends on epigenetic permissiveness and the spatial organization of the genome. Chromatin is not a passive spool of DNA. It is folded into topologically associating domains, or TADs, insulated neighborhoods in which enhancers preferentially contact the promoters they regulate. Structural maintenance of chromosomes complexes, chiefly cohesin, extrude DNA loops that bring distant regulatory elements together, while the insulator protein CTCF anchors domain boundaries. The WAPL cohesin release factor limits how far loops extend, tuning the overall folding landscape. When any of these components are altered, enhancers can be rewired onto inappropriate promoters, a mechanism long implicated in oncogene activation across many cancers.

HPV integration into the host genome is where viral biology and chromatin architecture collide. Integration is not a random insertion event; it frequently disrupts host regulatory regions and places viral and host sequences into new cis-regulatory relationships. Recent work cited in the review shows that the cis-regulatory effect of HPV integration is constrained by pre-existing host chromatin architecture, meaning the local folding context determines which genes a viral integration event can actually activate. Long-read sequencing of cervical cancer cell lines has revealed the structural complexity of these integration junctions, and genome-wide analyses have documented allele-specific impacts of viral-human rearrangements on cancer genome regulation. In effect, the virus hijacks the host’s own enhancer-promoter wiring, and the resulting rewiring can amplify MYC and E2F-centered transcriptional programs that drive uncontrolled proliferation.

The review gives particular attention to MYC, the transcription factor whose amplification has been detected even in preinvasive cervical lesions. MYC operates as a transcriptional amplifier, and tumors with rewired enhancer landscapes can become addicted to this sustained transcriptional output, a concept known as transcriptional addiction. That dependency creates a therapeutic opening. Bromodomain-containing protein 4, a BET family protein that recruits transcriptional machinery to active enhancers, has emerged as a druggable node: experimental studies show that BRD4 inhibition suppresses HPV16 E6 expression and enhances chemotherapy response, and separate work demonstrates that BRD4 inhibition sensitizes cervical cancer cells to radiotherapy by attenuating DNA repair. Early-phase clinical trials of MYC-targeting approaches in solid tumors, such as the peptide-based OMO-103, suggest that the long-undruggable MYC axis is finally becoming addressable.

Cohesin dynamics add another layer of vulnerability. The authors highlight their own prior finding that WAPL, the cohesin release factor, can induce cervical intraepithelial neoplasia in experimental models even without HPV E6 and E7, when modulated by estrogen signaling. This is a striking result because it implies that perturbing the genome’s folding machinery alone can push cervical epithelium toward premalignant states. Conversely, it suggests that cervical cancers may develop dependencies on specific cohesin regulators to maintain their malignant chromatin configuration. Recent single-molecule imaging of loop extrusion in living cells and studies showing extensive mutual influence among SMC complexes are refining how researchers understand these folding dynamics, and the review argues that such dependencies should be systematically screened in cervical cancer models using CRISPR perturbation and dependency mapping resources such as DepMap.

Chromatin remodeling complexes themselves are also implicated. Loss of ARID1A, the AT-rich interaction domain 1A subunit of the SWI/SNF complex, has been linked to tumor progression and adverse prognosis in cervical cancer, and emerging clinical data suggest that ARID1A and B2M mutations, together with antigen presentation pathway status, may predict response to definitive chemoradiotherapy. Histone modification enzymes, including the polycomb methyltransferase EZH2 and the demethylase KDM6A, are altered in HPV E6/E7-expressing keratinocytes, indicating that viral oncoproteins reprogram the epigenome from the earliest stages of infection. Three-dimensional chromatin analyses have additionally identified the transcription factor Sp1 as a mediator that programs and reprograms HPV-host epigenetic architecture in cervical cancer, providing a concrete molecular handle on how viral and host regulatory systems become intertwined.

Non-genetic plasticity is a recurring theme in the review’s account of therapeutic resistance. Cancer cells can evade drugs by reprogramming their transcriptional states without any new mutation, and rare pre-existing cell variants can seed drug-induced reprogramming within heterogeneous populations. Epigenetic plasticity is increasingly recognized as a hallmark that fuels tumor evolution while simultaneously exposing weaknesses. In cervical cancer specifically, single-nucleus and single-cell RNA sequencing studies have revealed heterogeneous microenvironments and distinct drug responses between squamous cell carcinoma and adenocarcinoma, while spatial transcriptomics is mapping how cancer-associated fibroblasts and immune cells shape the transcriptional landscape. Context-dependent signaling through PI3K-AKT, RAS-ERK, NOTCH1, and the Hippo pathway effectors YAP and TAZ, whose roles vary by HPV type, cooperates with chromatin state to determine whether a cell tolerates treatment or dies.

The tumor microenvironment completes the resistance circuit. CXCL8, a chemokine produced within the inflammatory milieu, has been shown to be essential for acquired radioresistance in cervical cancer cells and is proposed as a therapeutic target. HPV-mediated immune evasion mechanisms, the composition of the immune microenvironment, and the cancer-immune set point all influence how patients respond to the checkpoint inhibitor pembrolizumab, which in the phase 3 KEYNOTE-A18 trial improved outcomes when added to chemoradiotherapy for high-risk locally advanced disease. The review argues that chromatin-informed biomarkers, such as enhancer landscapes and chromatin accessibility profiles measured by ATAC-seq, ChIP-seq, and CUT&Tag, should be integrated with microenvironmental data to stratify patients more accurately than viral status alone allows.

Methodologically, the authors lay out an experimentally testable framework that leans on public datasets from The Cancer Genome Atlas and the Gene Expression Omnibus, perturbation-guided prioritization using CRISPR activation and interference screens, and computational tools including compositional perturbation autoencoders and in silico perturbation methods that predict cellular responses to genetic and pharmacological interventions. Multimodal artificial intelligence approaches that combine imaging, genomic, and clinical data are highlighted as a route to precision management, and network pharmacology offers a way to target causal resistance mechanisms rather than symptoms. Crucially, the framework depends on experimentally faithful models: authenticated cervical cancer cell lines, patient-derived organoids that recapitulate cervical tissue dynamics and viral oncogenesis, and patient-derived xenograft-style cultures that can predict sensitivity to chemotherapy and radiation.

The significance of this review lies in its reframing of HPV-driven cervical cancer as a disease of coupled viral and host genome regulation. Rather than treating E6 and E7 expression as the whole story, it positions chromatin architecture, enhancer rewiring, cohesin dynamics, and epigenetic plasticity as the machinery that converts viral checkpoint disruption into stable, adaptable, treatment-resistant malignancy. If the proposed framework holds up under experimental scrutiny, chromatin-informed stratification could identify which patients need intensified or combination therapy, while vulnerabilities in BET proteins, MYC signaling, cohesin regulators, and microenvironmental cytokines could yield rational combination strategies. For a cancer that remains a major global cause of mortality despite vaccination and screening, shifting the therapeutic lens from the viral oncogenes alone to the three-dimensional regulatory genome they exploit may prove a consequential conceptual advance.

Subject of Research: Host chromatin architecture and 3D genome rewiring in HPV-driven cervical cancer and therapeutic resistance

Article Title: Host chromatin architecture in HPV-driven cervical cancer: molecular mechanisms and therapeutic resistance

Article References: Kumagai, K., Suzuki, Y., Kitahara, K., Chiba, A., & Yajima, H. (2026). Host chromatin architecture in HPV-driven cervical cancer: molecular mechanisms and therapeutic resistance. Medical Oncology, 43(11), Article 324. https://doi.org/10.1007/s12032-026-03445-w

Image Credits: AI Generated

DOI: 10.1007/s12032-026-03445-w

Keywords: HPV, cervical cancer, chromatin architecture, 3D genome, enhancer rewiring, cohesin, WAPL, MYC, BRD4, therapeutic resistance, epigenetic plasticity, tumor microenvironment

The new review, authored by Shun-Ran Li, Meng-Qian Yu, and colleagues at Hangzhou Normal University and collaborating institutions, systematically surveys the explosion of dual- and multi-target degraders reported between 2023 and 2026. Its central premise is that complex diseases rarely depend on a single molecular culprit. Cancer and neurodegenerative disorders are governed by redundant and compensatory signaling networks, so when one driver protein is eliminated, others rush to fill the gap. Conventional single-target PROTACs, however powerful, can be undermined by this biological backup system. Dual PROTACs attempt to solve the problem in a single chemical entity, collapsing what would otherwise be a combination of two drugs into one compound with one set of pharmacokinetics.

The authors organize the growing catalog of dual degraders into two broad design classes. The first targets homologous proteins within the same family, where structural similarity can be exploited by a single warhead that binds both. Cyclin-dependent kinases have been a particular focus, with dual degraders reported for CDK4/6, CDK2/5, and CDK12/13, the latter exemplified by the orally bioavailable triple-negative breast cancer candidate DN1679. The BCL-2 family of apoptosis regulators has yielded dual BCL-2/BCL-xL degraders with improved anti-leukemic activity, and the field has now seen first-in-class degraders for the bromodomain proteins BAZ2A and BAZ2B as well as dual histone deacetylase degraders, including HDAC3/HDAC8 molecules that revealed new roles for histone acetylation in gene regulation.

The second, and pharmacologically more ambitious, class targets two distinct proteins sitting on different but interconnected disease pathways. Here the review catalogues an impressive roster: ERα/aromatase degraders designed to overcome endocrine-resistant breast cancer by hitting both the receptor and the enzyme that produces its activating estrogen; α-synuclein/tau degraders aimed at the protein aggregates that define Parkinson’s and Alzheimer’s disease; BET/HDAC and CBP/BRD4 degraders that combine epigenetic readers and erasers in one molecule; PI3K/mTOR degraders that suppress the entire eponymous survival pathway; and FLT3/CHK1 degraders that pair an oncogenic kinase with a checkpoint kinase to attack acute myeloid leukemia from two directions.

The technical heart of the review lies in its dissection of structure-activity relationships. Linker chemistry is where dual PROTACs live or die. Because a single molecule must accommodate two target-binding events, the linker length, attachment point, and flexibility determine not only potency but the ternary geometry between target, PROTAC, and E3 ligase that licenses ubiquitin transfer. Several case studies illustrate the point. Dual BCL-xL/BCL-w degraders were built by exploiting the bis(sulfonyl)benzene ring of the clinical inhibitor ABT-263 as a linkage vector, showing how careful warhead decoration can convert a blocker into a degrader. In the FLT3/CHK1 program, systematic linker scans revealed how marginal changes in length flipped degradation selectivity between the two kinases. The authors emphasize that hook effects, hook-like concentration dependence in which excess PROTAC saturates both binding sites separately and aborts the ternary complex, remain a persistent design trap requiring careful dose-response characterization.

E3 ligase selection emerges as another decisive variable. Most reported dual degraders recruit either the von Hippel-Lindau (VHL) ligase or cereblon (CRBN), reflecting the maturity of their ligand chemistries. CRBN-recruiting degraders derived from pomalidomide and related immunomodulatory drugs have proven especially productive for kinases and transcriptional regulators, while VHL ligands dominate among cytosolic and nuclear targets. But the review is blunt about the field’s narrow toolkit: the reliance on just two or three E3 ligases limits tissue selectivity, constrains the design space for dual targets, and contributes to off-target degradation of neo-substrates such as IKZF1 and IKZF3. Expanding the E3 ligase repertoire, including tumor-selective or tissue-specific ligases, is flagged as a priority for next-generation design.

Among the milestones the review highlights are the first dual degraders aimed at non-kinase epigenetic regulators and, strikingly, at protein aggregates themselves. Degraders capable of clearing α-synuclein and tau aggregates simultaneously represent a conceptual breakthrough for neurodegeneration, because both misfolded proteins cross-seed one another and together drive pathology in diseases such as dementia with Lewy bodies and Alzheimer’s. The authors note that these designs repurposed aggregation-binding scaffolds, such as thioflavin-derived amyloid ligands, as warheads, demonstrating that even supramolecular pathological assemblies can be brought into the reach of the ubiquitin-proteasome system. In parallel, dual GSPT1/BRD4 degraders exploit cereblon-mediated translational termination factor degradation alongside epigenetic transcriptional collapse to kill leukemia cells through mechanistically independent routes.

The translational horizon is coming into view. The first PROTAC, vepdegestrant, has moved targeted degradation into approved oncology practice, and clinically advanced single-target degraders have validated the modality’s core principles. Dual degraders now face the harder test of converting dual potency into dual efficacy with an acceptable safety profile. The review identifies pharmacokinetics as the chief obstacle: dual PROTACs are large, often exceeding the classic rule-of-five boundaries for oral absorption, and their high polarity and molecular weight challenge permeability, metabolic stability, and brain penetration. Off-target toxicity arising from polypharmacology is a second concern, since the same warhead promiscuity that enables dual engagement can degrade unintended proteins. Strategies such as introducing one-carbon bridges to lower lipophilicity, incorporating molecular glue features into PROTAC scaffolds, and exploiting CD36-mediated endocytosis to improve cellular uptake are among the emerging countermeasures surveyed.

What the review ultimately delivers is a map. By consolidating the 2023 to 2026 literature into a coherent framework of homologous versus cross-pathway dual targets, and by extracting transferable SAR lessons on warhead choice, linker optimization, and E3 ligase pairing, the authors have given medicinal chemists a practical playbook for the next round of design. If the remaining pharmacokinetic and selectivity problems can be tamed, dual PROTACs could compress combination therapy into a single pill, offering patients with complex, drug-resistant diseases a weapon that dismantles two pillars of pathology at once. For a field that has already taught medicine to delete proteins rather than merely inhibit them, degrading disease networks two nodes at a time may be the logical, and inevitable, next act.

Subject of Research: Development of dual PROTACs that simultaneously degrade two disease-related proteins for therapeutic applications in cancer and neurodegenerative disease.

Article Title: Recent advances of dual PROTACs for potential therapeutic applications

Article References: Li, S.-R., Yu, M.-Q., Du, B.-Q., Jin, K.-J., Chen, S.-X., Hui, Z., Zhang, H., Mao, N.-D., Gao, Y., & Ye, X.-Y. (2026). Recent advances of dual PROTACs for potential therapeutic applications. Molecular Diversity. https://doi.org/10.1007/s11030-026-11734-9

Image Credits: AI Generated

DOI: 10.1007/s11030-026-11734-9

Keywords: PROTACs, targeted protein degradation, dual degraders, ubiquitin-proteasome system, E3 ubiquitin ligase, cancer therapy, neurodegenerative disease, BCL-2, BRD4, CDK inhibitors, structure-activity relationships, drug discovery