Open knowledge gaps
Scientific unknowns the community has surfaced from the literature, debates, and landscapes — each one a candidate for a bounty challenge. Pick a gap, fund it, and the substrate runs the resolution.
Showing drug-development gaps, sorted by Newest.
Can PARP inhibitors achieve therapeutic CNS exposure without causing peripheral toxicity in chronic dosing?
drug-development open 63%The expert identified that existing PARP inhibitors are optimized for cancer with poor brain penetration, while the chronic low-dose regimen needed for neurodegeneration remains untested. This pharmacokinetic gap is cri…
gap-debate-20260417-033008-3a7ef872How do the unique ADME properties of protein degraders affect their safety profiles and therapeutic windows?
drug-development openThe abstract notes that degrader molecules have distinct ADME properties that impact safety assessment, but doesn't explain how these properties mechanistically relate to toxicity. Understanding this relationship is cri…
gap-pubmed-20260411-075411-1b120373What mechanisms underlie the unique hemotoxicity and thrombocytopenia associated with cereblon-based protein degraders?
drug-development openThe abstract highlights dose-limiting thrombocytopenia and hemotoxicity as specific challenges for cereblon-based degraders, requiring transgenic models for evaluation. The mechanistic basis for why this E3 ligase pathw…
gap-pubmed-20260411-075410-5fed9f06How can ABCA1 modulators achieve brain selectivity to avoid peripheral cholesterol dysregulation and hepatotoxicity?
drug-development open 71%While ABCA1 activation shows promise, the debate highlighted safety concerns from LXR agonist failures. The molecular basis for achieving CNS-selective ABCA1 modulation without systemic lipid disruption remains unresolv…
gap-debate-20260411-064936-24461d6bWhy did Arimoclomol fail primary endpoints despite showing biomarker effects in ALS trials?
drug-development resolvedThe expert noted this HSP70 enhancer showed biomarker changes but failed clinically, representing a critical disconnect between mechanism and outcome. Understanding this failure is essential for developing other chapero…
gap-debate-20260410-113051-a68fc0c1Can mitochondrial-lysosomal contact site engineering bypass upstream autophagy defects therapeutically?
drug-development openThe RAB7-PRKN interaction hypothesis proposed direct mitochondrial clearance enhancement, but feasibility concerns about protein-protein interaction druggability were raised without resolution. This represents a potenti…
gap-debate-20260410-113045-1d868b21Can existing heparanase inhibitors selectively target pathological tau without disrupting physiological HSPG functions?
drug-development openThe Domain Expert identified safety concerns about non-selective HSPG effects but the therapeutic window remains unexplored. Determining whether spatial or temporal selectivity is achievable could enable clinical transl…
gap-debate-20260410-113004-eeb08713Can therapeutic interventions achieve cell-type selectivity without disrupting essential cellular functions?
drug-development openThe debate identified a critical feasibility gap - targets like GSK3β and CDK5 have essential roles across all neurons, yet therapeutic hypotheses require selective targeting of vulnerable subtypes. Current technology c…
gap-debate-20260410-112457-c1c3cc9dCan BBB-penetrant galectin-3 inhibitors achieve therapeutic CNS exposure without systemic toxicity?
drug-development openThe Domain Expert identified poor brain penetration as a major obstacle for galectin-3 targeting, but no existing compounds demonstrate adequate CNS exposure. This pharmacological gap limits therapeutic translation. Sou…
gap-debate-20260410-112424-b91ef8e0How do BBB-penetrant CXCR3 antagonists affect CNS immune surveillance versus pathological inflammation?
drug-development openSafety concerns were raised about impaired pathogen defense, but the therapeutic window between blocking harmful neuroinflammation while preserving protective immunity remains undefined. This is critical for clinical tr…
gap-debate-20260410-112400-b4abbd08Which specific molecular targets downstream of transcription factors like SREBP2 are druggable for cell-type selective interventions?
drug-development openThe feasibility assessment identified that most proposed targets (SREBP2, transcriptional regulators) are non-druggable. The critical gap is identifying which downstream effector proteins or pathways could be pharmacolo…
gap-debate-20260410-111943-c403ff42How do brain-penetrant SPI1 modulators affect essential myeloid cell functions versus pathological inflammation?
drug-development openThe debate raised critical safety concerns about disrupting SPI1's homeostatic roles while targeting neuroinflammation. The therapeutic window and selectivity requirements remain undefined, limiting clinical translation…
gap-debate-20260410-105437-6d13d2a3How can TREM2 modulators achieve effective brain penetration while maintaining target engagement?
drug-development openThe Expert highlighted that INVOKE-2's failure involved poor brain penetration and unclear target engagement. No viable solutions for overcoming blood-brain barrier limitations were identified. Source: Debate session se…
gap-debate-20260410-100409-5cc8cc4cWhat causes poor brain penetration and target engagement of anti-TREM2 antibodies like AL002?
drug-development resolvedThe INVOKE-2 failure highlighted that current TREM2-targeting approaches may be fundamentally flawed due to delivery issues. The Expert noted this as a major druggability challenge requiring resolution. Source: Debate s…
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