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Overview

Tags

Neoplasms

Digestive System Disorders

Respiratory Diseases

Small molecule drug

Disease domain score

A glimpse into the focused therapeutic areas

Technology Platform

Most used technologies in drug development

Targets

Most frequently developed targets

Disease Domain	Count

Neoplasms	9

Top 5 Drug Type	Count

Small molecule drug	9

Top 5 Target	Count

Notch-1(Neurogenic locus notch homolog protein 1)	3
CK1α(casein kinase 1 alpha 1)	2
Wnt	1
CTNNB(Beta catenins)	1
c-Myc(Myc proto-oncogene protein)	1

AbstractAcute lymphoblastic leukemia (ALL) is a leading cause of cancer-related death in children and adolescents, and cure rates for relapsed/refractory ALL remain dismal, highlighting the need for novel targeted therapies. To identify genome-wide metabolic-stress regulated genes, we used RNA-sequencing in ALL cells treated with AICAR, an AMPK activator. RNA-sequencing identified the immediate early genes (IEGs) as a subset of genes downregulated by AICAR. We show that AICAR-induced IEGs downregulation was blocked by an adenosine uptake inhibitor indicating AICAR was responsible for IEGs reprogramming. Using pharmacologic and genetic models we established this mechanism was AMPK-independent. Further investigations using kinase assays, PKD/PKC inhibitors and rescue experiments, demonstrated that AICAR directly inhibited PKD kinase activity and identified PKD as responsible for IEGs downregulation. Mechanistically, PKD inhibition suppressed phosphorylation and nuclear export of class IIa HDACs, which lowered histone H3 acetylation and decreased NFκB(p65) recruitment to IEGs promoters. Finally, PKD inhibition induced apoptosis via DUSP1/DUSP6 downregulation eliciting a DNA damage response. More importantly, ALL patient cells exhibited the same PKD-HDACs-IEGs–mediated mechanism. As proof of principle of the therapeutic potential of targeting PKD, we established the in vivo relevance of our findings using an NSG ALL mouse model. In conclusion, we identified a previously unreported PKD-dependent survival mechanism in response to AICAR-induced cellular stress in ALL through regulation of DUSPs and IEGs' expression.Implications:PKD mediates early transcriptional responses in ALL cells as an adaptive survival mechanism to overcome cellular stress.

15 Feb 2019·Clinical Cancer Research

A CK1α Activator Penetrates the Brain and Shows Efficacy Against Drug-resistant Metastatic Medulloblastoma

Article

Author: Orton, Darren ; Ayad, Nagi G. ; Weiss, William A. ; Kasahara, Noriyuki ; Collins, Sara ; Long, Jun ; Yang, Fan ; Li, Bin ; Robbins, David J. ; Capobianco, Anthony J. ; Roussel, Martine F. ; Rodriguez-Blanco, Jezabel ; Shen, Chen ; McCrea, Heather J.

AbstractPurpose: Although most children with medulloblastoma are cured of their disease, Sonic Hedgehog (SHH) subgroup medulloblastoma driven by TRP53 mutations is essentially lethal. Casein kinase 1α (CK1α) phosphorylates and destabilizes GLI transcription factors, thereby inhibiting the key effectors of SHH signaling. We therefore tested a second-generation CK1α activator against TRP53-mutant, MYCN-amplified medulloblastoma.Experimental Design: The ability of this CK1α activator to block SHH signaling was determined in vitro using GLI reporter cells, granular precursor primary cultures, and PATCHED1 (PTCH1)-mutant sphere cultures. While in vivo efficacy was tested using 2 different medulloblastoma mouse models: PTCH1 and ND2:SMOA1. Finally, the clinical relevance of CK1α activators was demonstrated using a TRP53-mutant, MYCN-amplified patient-derived xenograft.Results: SSTC3 inhibited SHH activity in vitro, acting downstream of the vismodegib target SMOOTHENED (SMO), and reduced the viability of sphere cultures derived from SHH medulloblastoma. SSTC3 accumulated in the brain, inhibited growth of SHH medulloblastoma tumors, and blocked metastases in a genetically engineered vismodegib-resistant mouse model of SHH medulloblastoma. Importantly, SSTC3 attenuated growth and metastasis of orthotopic patient-derived TRP53-mutant, MYCN-amplified, SHH subgroup medulloblastoma xenografts, increasing overall survival.Conclusions: Using a newly described small-molecule, SSTC3, we show that CK1a activators could address a significant unmet clinical need for patients with SMO inhibitor–resistant medulloblastoma, including those harboring mutations in TRP53.

27 Jun 2017·Science SignalingQ1 · BIOLOGY

Differential abundance of CK1α provides selectivity for pharmacological CK1α activators to target WNT-dependent tumors

Q1 · BIOLOGY

Article

Author: Nguyen, Dao M. ; Shen, Chen ; Lee, Ethan ; Kirkbride, Kellye C. ; Marchetti, Floriano ; Thorne, Curtis ; Guerra, Marcy L. ; Long, Jun ; Orton, Darren ; Jin, Ke ; Neitzel, Leif R. ; Robbins, David J. ; Astudillo, Luisana ; Wang, Zhiqiang ; Chen, Xi ; Abreu, Maria T. ; Doundoulakis, Thomas ; Li, Bin ; Fei, Dennis Liang ; Cobb, Melanie H. ; Capobianco, Anthony J. ; Zaias, Julia ; Sands, Laurence R. ; Rodriguez-Blanco, Jezabel

A small-molecule CK1α activator inhibits the growth of WNT-driven intestinal tumors without toxicity to normal epithelium.

100 Deals associated with StemSynergy Therapeutics, Inc.

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100 Translational Medicine associated with StemSynergy Therapeutics, Inc.

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Pipeline

Pipeline Snapshot as of 23 Nov 2024

The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

Preclinical

9

2

Other

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Current Projects

Drug(Targets)	Indications	Global Highest Phase

SST-024 ( CK1α )	Adenomatous Polyps More	Preclinical
SST-215 ( Wnt )	Non-Small Cell Lung Cancer More	Preclinical
SSTB-178 ( CTNNB )	Neoplasms More	Preclinical
SSTK-214 ( PRAG1 )	Neoplasms More	Preclinical
SSTN-302 ( Notch-1 )	Neoplasms More	Preclinical