New Targets: Drug Hunters Assemble

Jumpman finds five new targets with a 2017 genetics-based approach: SP1, HDAC2, NR3C1 (GCR-alpha), BCL2, and PTGIR

Our favorite mouse Ghter teaches us IGFBP3 is upregulated in balding scalps

Jumpman repor ts RSPO3 is downregulated 8-fold by DHT exposure in DPC cells, granted it’s measured in a 2D cell culture

Ndimension wonders what would happen if he upregulated PGE2 four teen times above his current level

Synthetic Pug, Jumpman, and Metabobbly teach us IL-6 may promote hair loss exclusively through TGFb TGFb is required for hair growth too though, and so shouldn’t be a direct target

Jumpman thinks PGD2 is a money sink, for a bunch of diseases

Jumpman shoots down GSKb3 as a target It's probably not a great mechanism because it's downstream of Wnt receptors, and may actually result in the degradation of Fzd Wnt receptors by recruiting Fzd degrading proteins, par ticularly in AGA scalp where the protein (RSPO) that suppresses Fzd degrading proteins is already low.

Visangle and Jumpman identify that IRX5 knockout causes hair loss by downregulating DNA repair regulators BRCA1 and FOXM1 and upregulating FGF18 In tandem, differentially-open chromatin regions in IRX5+ cells include NFATc1, LHX2, and JUND. Are any of the targets wor th our pursuit?

FGF targeting needs to be done correctly, warns Jumpman: “FGFR inhibition is not great. It needs to be modulated in just the right way You want to block the negative regulators FGF5 and maybe FGF18 Downregulate FGF23 and maybe FGF21 but not block them Blocking FGF18 only par tially rescued anagen delay in IRX5 knockout ” Benjels wants to inhibit FGF-18

Synthetic Pug wants to look at NOX2 inhibition using GSK2795039 Downregulating NOX reduces ROS, consequently mitigating cellular senescence The paper identifies DPI, VAS2870, VAS3947, and tat-gp91ds as the most convincing NOX antagonists. Potential Dingo wonders about the safety profile of NOX inhibitor Isuzinaxib–it’s about $600 for a 6 month oral supply

Jumpman identifies that AC010789.1, a long non-coding RNA, delays androgenic alopecia progression by promoting the proliferation and differentiation of hair follicle stem cells (HFSCs) and downregulating miR-21-5p and TGF-β1 expression, while upregulating the Wnt/β-catenin signaling pathway

SyntheticPug identifies elastin as a potential marker to monitor, highlighting that normalizing the protein is key Elastin is essential for the tissue remodeling that takes place at the intersection of the arrector pilli and outer root sheath (ORS). Its overregulation likely blocks follicle growth and upregulates inflammation, while its underregulation causes detachment from the arrector pilli muscle

Ndimension found that Nanog could have positive effects on hair follicle stemness through bone morphogenetic protein (BMP) signaling and well-known growth factors Sox2 and Oct4)

Benjels drops new study design for 3aHSD. Long live sulforaphane

We receive our monthly PAI-1 update from Pubehead: Eirion made a royalty milestone payment to Renaissance six weeks ago, earning clearance to begin Phase 1 clinical trials Any day now–the trial should show up in the registry. To achieve maximum PAI-1 inhibition, Jumpman recommends apj agonist along with a pde5 inhibitor. Vincent repor ts on TM5441’s metabolites and mechanisms of action in non-hair diseases