aacrjournals.org/cancerdiscov...

Things I like about this:
- Use of phenotypic screening
- Upfront counterscreening for selectivity
- Notable CAF-mediated MOA:⬆️ #ECM organization, collagen metabolism
- Immediate translation into trials

Also how long did this all take to do?... #medchem

Lots to be gleaned from this:

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

But importantly appears that allostery in #kinases can be underestimated by cell-free kinase panels, especially for non-type I inhibitors #medchem

The therapeutic potential of orphan adhesion G-protein-coupled receptors - Nature Reviews Drug Discovery Adhesion G-protein-coupled receptors (aGPCRs) have been implicated in multiple human pathologies, yet no drugs targeting these receptors are currently approved. This Review provides an overview of the...

#GPCR remain a major target of small molecules, and this review rightly demonstrates the promise of drugging adhesion GPCRs. This could be especially impt in cancer, where we now appreciate the #TME, #ECM, integrin signaling, mechanotransduction, etc.

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

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...

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

As a former #peptide chemist turned small mol chemist, I know this took tons of work. Lessons learned re: peptides:

- ⬆️Lipophilic = better always, generally
- PPB may be key
- PK = major issue

Also SPR exp w/ cyclins...would love to know the method

Extracellular matrix sensing regulates intratumoral heterogeneity of autophagic flux Human pancreatic cancer cells sense specific components of the ECM to fine-tune their autophagy flux levels, conferring the ability to coordinate proliferation, survival, and responsiveness to chemoth...

Work like this further convinces me the #ECM is more than a scaffold - it is a signal

www.cell.com/cell/fulltex...

A Near-Infrared Fluorogenic Spray Probe for Rapid and Wash-Free Intraoperative Nerve Imaging Intraoperative nerve injury remains a major surgical challenge. Rapid, wash-free nerve visualization is highly desirable for fluorescence image-guided surgery (FIGS), yet existing probes lack spray co...

I can't tell you how many surgeries I've been in where we've debated for quite some time if a structure was vessel or nerve...

Really cool #medchem work that I think has translational potential

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

Emerging landscape of KRAS inhibitors in cancer treatment Alterations in KRAS, NRAS, and HRAS occur in roughly 20% of patients with cancer, making RAS one of the most intensively studied oncogenic targets. Th…

Nice review of #KRAS inhibitors: www.sciencedirect.com/science/arti...

Interesting that MRTX1133 development halted due to PK - with improved pre-clin testing, PK issues rarely lead to failure in trials

And KRAS amp seems to be major mech. of resistance - how can we exploit/prevent this?

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