Erik Faber MD PhD

2/2: Unfortunately I couldn't find the #SPR Kd data and methods - would be important to know how cyclin was able to be stable in its isolated form for such measurements, given the notorious aqueous instability of lone cyclins without their binding partners

Orally Bioavailable Cyclin A/B RxL Inhibitors: Optimization of a Novel Class of Macrocyclic Peptides That Target E2F-High and G1–S-Checkpoint-Compromised Cancers Cyclins A and B bind and activate their cognate cyclin-dependent kinase (CDK) to regulate progression through the S and G2/M phases of the cell cycle, respectively. Cyclins recruit substrates and regu...

1/2: I'm not too old but I never thought I'd see a believable #cyclin targeting drug in my lifetime.

Kudos to the effort it took to make this peptide look more like a small molecule and we'll see what happens in the clinic.

pubs.acs.org/doi/10.1021/...

CD19 CAR-T cells for treatment-refractory autoimmune diseases: the phase 1/2 CASTLE basket trial - Nature Medicine In the phase 1/2 CASTLE basket trial, autologous CD19 CAR-T cell therapy in patients with treatment-refractory systemic lupus erythematosus, systemic sclerosis or idiopathic inflammatory myopathy was ...

Is CAR-T the future for the treatment of refractory debilitating rheumatological disease? I think so

We'll see if the lower toxicity in this population (no ICANS, lower grade CRS) persists with larger studies

www.nature.com/articles/s41...

I find these conclusions very believable - it should make us all think about we can remain accessible to other team members while maintaining boundaries, and the role of secure chat. And of course, we should always be working to affect systemic change

rdcu.be/e43kQ

Human assembloids recapitulate periportal liver tissue in vitro - Nature Hepatocyte organoids derived directly from human tissue enable long-term hepatocyte expansion and can be combined with portal mesenchyme and cholangiocyte organoids to form a donor-specific periportal...

Much of combatting future human disease will require a keen focus on the liver. Work like this to develop better #organoid models will be key- e.g. what could be recapitulated/uncovered with the addition of cancer cells to these sorts of models?

www.nature.com/articles/s41...

GTP release-selective agonists prolong opioid analgesic efficacy - Nature Mu opioid receptor agonists with a preference for the non-GTP-bound state of the G protein promote GTP release, thereby potentiating antinociceptive effects of drugs such as morphine and fentanyl with...

Love this kind of work that connects conformational selectivity of a drug to its target with possibly improved therapeutic properties #medchem

www.nature.com/articles/s41...

Detection of undiagnosed liver cirrhosis via AI-enabled electrocardiogram: a pragmatic, cluster-randomized clinical trial - Nature Medicine In a trial involving 45 clinics and 15,596 visits, the use of an AI-based screening tool applied to ECG for opportunistic detection of advanced chronic liver disease led to a significant increase in n...

Still wild to me that #EKG findings could be informative for liver disease/ #cirrhosis - must be so much granular data in EKG tracings that we underappreciate

www.nature.com/articles/s41...

Fasting boosts breast cancer therapy efficacy via glucocorticoid activation - Nature Beneficial effects of fasting combined with endocrine therapy for oestrogen receptor-α-expressing breast cancers can be recapitulated using exogenous glucocorticoid receptor ligands instead of fasting...

Interesting work but just wish the title had ended with "in mice"

www.nature.com/articles/s41...

The NIH has lost its scientific integrity. So we left “We can no longer lend our credibility to an organization that has lost its integrity,” write four scientists and administrators who recently resigned from the NIH.

www.statnews.com/2026/01/10/n...

Nice review of state of #PDAC models: www.nature.com/articles/d41...

Glad to see folks are working on this incredibly relevant clinical problem of #CIPN - more funding for this kind of work, please!

pubs.acs.org/doi/10.1021/...

A rare and impt dataset for #PDAC to analyze both primary + met lesions. Most meaningful may be the matched specimens, considering interpatient variability. E.g. the myCAF trend for the matched was the opposite of that from the composite analysis...

aacrjournals.org/cancerres/ar...

Therapeutic Use of Cannabis and Cannabinoids This review discusses current evidence about the therapeutic use of cannabis and cannabinoids in adults, potential harms, and evidence-based clinical guidance, including pretreatment screening and add...

Thought this review on clinical uses of CBD/THC was nicely done - balancing potential benefits (likely modest at best, strength of evidence is wanting) with some of the oft ignored potential risks, including some like increased CV disease I was unaware of

jamanetwork.com/journals/jam...

Cholangiocarcinoma 2026: status quo, unmet needs and priorities - Nature Reviews Gastroenterology & Hepatology In this Consensus Statement, an international panel of experts present an overview of the latest developments in the field of cholangiocarcinoma. A set of consensus recommendations and research priori...

Nice review of #CCA, especially these outlined research priorities: 1) investigation into modulating the TME to expand therapeutic targets and 2) assessing if patient-derived 3D models can be used to tailor therapeutic approaches

www.nature.com/articles/s41...

Allosteric binding cooperativity in kinases signaling, signalopathies, and drug development Protein kinases catalyze the transfer of phosphate groups from ATP to specific substrates, initiating, modulating, or terminating signaling cascades. …

A nice review on #cooperativity in #kinases - I think exploiting these properties may be the way we can forgo some of the tox that is dose limiting in the clinic associated with kinase inhibitors #medchem

www.sciencedirect.com/science/arti...

Drug screening in 3D microtumors reveals DDR1/2-MAPK12-GLI1 as a vulnerability in cancer-associated fibroblasts Interactions between cancer cells and surrounding stromal cells are critical for tumor biology and treatment response. We compare drug screening resul…

Always intriguing to find differences between drug response in 2D v. 3D models. Here, more drugs are efficacious in 3D - a bit counterintuitive since translation of efficacy from preclinical work relying on 2D models is historically poor... #medchem

www.sciencedirect.com/science/arti...

Human organoids as 3D in vitro platforms for drug discovery: opportunities and challenges - Nature Reviews Drug Discovery Human organoids provide physiologically relevant, 3D models for studying disease mechanisms, drug efficacy and toxicity. This Review examines organoid generation methods, applications in preclinical d...

If all models are wrong, will #organoids prove to be the most useful? A nice review of how we can take next steps to better assess clinical efficacy of drugs in a preclinical setting #medchem www.nature.com/articles/s41...

Sodium Bicarbonate for Severe Metabolic Acidemia and Acute Kidney Injury This randomized clinical trial examines whether sodium bicarbonate infusion decreases day 90 all-cause mortality for patients with severe metabolic acidosis and moderate to severe acute kidney injury.

Age-old dilemma: HCO3 for AKI and met acidosis - Ya or Na? Still not life saving (need to reverse underlying etiology?) but less renal replacement needed

jamanetwork.com/journals/jam...

Circulating tumor DNA-guided adjuvant therapy in locally advanced colon cancer: the randomized phase 2/3 DYNAMIC-III trial - PubMed Adjuvant chemotherapy in stage III colon cancer provides uncertain benefit at the individual level. Circulating tumor DNA (ctDNA) may help refine risk-adjusted treatment selection. In this multicenter, randomized, phase 2/3 trial, patients with stage III colon cancer underwent ctDNA testing 5-6 week …

Impt for all of us ordering #ctDNA in #CRC: ctDNA-guided was NOT NON-inferior. Incredibly 1/2 ctDNA+ pts were escalated to FOLFOXIRI certainly w/o benefit - clearly we need better salvage treatments too

pubmed.ncbi.nlm.nih.gov/41115959/

Targeting G1–S-checkpoint-compromised cancers with cyclin A/B RxL inhibitors - Nature Dual cyclin A/B RxL inhibitors selectively kill small cell lung cancer cells and other cancer cells with high E2F activity.

I love a good #peptide inhibitor story, but given the expected poor #PK properties in the extended figures, I'd be willing to bet there's a small molecule-like metabolite driving most of this activity. Otherwise I worry there's something off-target #medchem

www.nature.com/articles/s41...

Discovery, Optimization, and Anticancer Activity of Lipid-Competitive Pleckstrin Homology Domain-Containing Family A Inhibitors Phosphoinositide signaling is a major cellular mechanism controlling cancer cell viability, proliferation, and survival. Yet, inhibition of lipid kinases that produce oncogenic phosphoinositides has a...

Such a great classic #medchem story. Going after these atypical targets (e.g. phosphoinositide/lipid/carbohydrate engagers) with creative biological validation is what patients need to experience better outcomes.

pubs.acs.org/doi/full/10....

Resolving fibrosis by stimulating HSC-dependent extracellular matrix degradation - PubMed Tissue fibrosis arises from a critical imbalance between the production and breakdown of extracellular matrix (ECM) components. Whereas current strategies predominantly focus on curbing ECM production...

Cool translational work about an important health topic. Another example of how physician scientists and chemists can collaborate to move the needle forward #medchem #mdphd #doubledocs

pubmed.ncbi.nlm.nih.gov/40864684/

Fulcrum Occupancy-Leverage Perturbation Strategy Enables Rapid Discovery of Potent CDK2-Cyclin A2 Interaction Inhibitors - PubMed Traditional strategies for developing small-molecule inhibitors of protein-protein interactions (PPIs) are time-consuming and often yield low success rates due to the flat and dynamic interfaces of PP...

2/2

pubmed.ncbi.nlm.nih.gov/40827837/

Disrupting CDK2/cyclin PPI like our work did ;) but via orthosteric inhibitors causing global conformational changes. However unclear why this works for cyclin A2 complexes but not cyclin E ones, and surprising given nM affinity b/w CDKs and cyclins #medchem

Speedy A governs non-homologous XY chromosome desynapsis as a unique prerequisite for XY loop-axis organization | The EMBO Journal imageimageIn mouse spermatocytes, the X and Y chromosomes undergo rapid non-homologous synapsis and desynapsis during early pachynema. This study reveals that X-Y desynapsis initiated by the atypical ...

Two new #CDK2 papers bringing me back to my PhD days (1/2):

www.embopress.org/doi/full/10....

More mechanistic studies of CDK2/Spy1 role in meiosis including impt SUN1 phos site. Still unclear if CDK2/Spy1 is most impt for scaffolding/localization or enzymatic activity, or, "por que no los dos?"

Adrenal Insufficiency in Adults: A Review This Review summarizes the pathophysiology of adrenal insufficiency and approaches to diagnosis, treatment, and prevention of adrenal crisis.

So...are there new cutoffs for AM cortisol that I shouldn't cort stim folks? Why the change?

jamanetwork.com/journals/jam...

Integrative genomic identification of therapeutic targets for pancreatic cancer Guo et al. perform a systematic assessment of genetic dependencies and cell surface targets in pancreatic adenocarcinoma, identifying biomarkers, mapping interpatient and intratumoral heterogeneity, a...

www.cell.com/cell-reports...

Property-Based Prediction Uncovers Intestinal Excretion as an Elimination Route of Small-Molecule Drugs Hepatic and renal pathways are traditionally considered the primary routes of drug clearance. However, emerging evidence highlights the significant role of direct intestinal excretion of unchanged drugs and metabolites. Intestinal excretion is often unrecognized due to complications arising from unabsorbed drugs and direct biliary excretion. Consequently, the extent and mechanisms of intestinal excretion remain systematically underexplored. Using bile duct cannulated rats, we investigated intestinal excretion for a library of drugs and proposed a predicative decision tree based on molecular descriptors. Mechanistically, passive permeability and efflux transporters emerged as key drivers of intestinal excretion in rats. We also demonstrated that modulating a single functional group can alter the clearance pathways between intestinal and biliary excretion. The insights into intestinal excretion as a major clearance pathway for metabolically stable small-molecule drugs provide a more comprehensive understanding for drug clearance and offer new considerations for drug design and pharmacokinetic assessment.

Provocative work - should we be dosing some drugs differently in patients with less bowel then? #medchem #PK

pubs.acs.org/doi/10.1021/...

Perspectives of biomedical trainees during a time of policy disruption - Nature Medicine Nature Medicine - Perspectives of biomedical trainees during a time of policy disruption

Interesting survey with lots of #mdphd #doubledocs representation. Sad observations:
- vast majority have changed career plans based on federal changes
- supportive environment = $ - even for those new to this career can see this

www.nature.com/articles/s41...

When Do You Need a Macrocycle, Anyway?

Tying a drug candidate structure around into a macrocycle is real work: so why bother doing for things like kinase inhibitors?

85% of all drug candidates that go into human trials fail. Expensively. This is the central fact of the entire research pharma industry.