Hypophosphatasia (HPP) is a rare genetic disorder that severely affects the development of bones and teeth due to defective mineralization. HPP causes poor skeletal development, fragile bones, early tooth loss and in older patients, clinically significant muscle weakness, fatigue and pain. The condition is known to affect tens of thousands of patients worldwide but is believed to be underdiagnosed in older patients.

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OC-1 is a first-in-class oral therapeutic currently progressing through GLP toxicology studies. It is expected to enter clinical trials in the second half of 2025. 

Since the initial approval of olaparib in 2014, PARP inhibitors have demonstrated utility as a therapeutic class for the treatment of certain cancers. Despite this success, first-generation PARP1/2 inhibitors, are known to cause significant toxicities, most commonly anemia, neutropenia, and thrombocytopenia, limiting their clinical applicability. Subsequent studies have indicated that PARP2 inhibition is associated with the observed hematologic toxicity. More recently, it has been demonstrated that inhibition of PARP1 alone is sufficient for synthetic lethality with homologous recombination (HR) deficiency, whereas PARP2 and PARP3 inhibition is dispensable.

 

Taken together, these findings suggest that a PARP inhibitor with improved selectivity for PARP1 over PARP2 and PARP3 would benefit patients by expanding the treatment opportunities for this important class of targeted therapy. Recent disclosures around selective PARP1 inhibitors show progress in the right direction. However, due to a lack of PARP1/2 selectivity at relevant exposures, these inhibitors may not sufficiently shift the balance of their activity away from unwanted bone marrow and hematologic toxicities.

 

Our approach builds on excellent selectivity over PARP2 at predicted therapeutic exposures to afford single-agent efficacy and maintain the optionality for combinations with other agents. We believe this profile will afford a best-in-class PARP1 inhibitor that is safe, durable and effective. It can be used as a single agent in HR deficient settings and can potentially be expanded for use in difficult-to-treat HR proficient settings when combined with platinum-based chemotherapy and other targeted agents.

Cyclin-dependent kinases (CDKs) are a family of serine/threonine protein kinases involved in cell cycle regulation (CDK1-4 and 6) and transcription modulation (CDK7-13, 19 and 20). Separate from other kinases, CDKs are generally activated by noncovalent association with their respective cyclins and phosphorylation by a CDK-activating kinase (CAK). Interest in CDKs and their role in cancer progression has led to the approval of four CDK-targeting medicines, all four being dual-inhibitors of CDK4/6.

 

Unlike other CDKs, CDK7 plays a role in both cell cycle regulation as well as transcription modulation, processes which are dysregulated in certain cancers. Together, the CDK7•Cyclin H•MAT1 complex serves as the CAK responsible for activating CDK1, 2, 4 and 6. CDK7 also activates transcriptional CDKs and modulates the transcription of important oncogenes and nuclear hormone receptors. Its central role in processes which govern the growth and progression of tumors makes CDK7 an important target in the treatment of cancer.

 

We are exploring multiple modalities towards CDK7 inhibition. Our inhibitors are effective against parental, as well as drug-resistant cancer cell lines. Excitingly, we have discovered a potent and brain penetrant CDK7 inhibitor that works across breast cancer phenotypes and could revolutionize the treatment paradigm for cancer patients with brain metastasis.