Pi­o­neer­ing Click Chem­istry in Hu­mans

This ar­ti­cle was pub­lished pri­or to the an­nounce­ment of the 2022 No­bel Prize in Chem­istry. Con­grat­u­la­tions to Dr. Bertozzi, Dr. Mel­dal, and Dr. Sharp­less.

Reimag­in­ing can­cer treat­ments

Can­cer is a lead­ing cause of death world­wide, ac­count­ing for near­ly 10 mil­lion deaths in 2020, which is near­ly one in six deaths. Re­cent­ly, we have seen in­cred­i­ble ad­vances in nov­el can­cer ther­a­pies such as im­mune check­point in­hibitors, cell ther­a­pies, and an­ti­body-drug con­ju­gates that have re­vamped can­cer care and im­proved sur­vival rates for pa­tients.

De­spite this sig­nif­i­cant progress in ther­a­peu­tic tar­get­ing, why are we still see­ing such a high mor­tal­i­ty rate? The rea­son is that promis­ing ther­a­pies are of­ten lim­it­ed by their ther­a­peu­tic in­dex, which is a mea­sure of the ef­fec­tive dose of a drug, rel­a­tive to its safe­ty. If we could broad­en the ther­a­peu­tic in­dices of cur­rent­ly avail­able med­i­cines, it would rev­o­lu­tion­ize can­cer treat­ments. We are still on the quest to find the ul­ti­mate can­cer med­i­cine – high­ly ef­fec­tive in sev­er­al can­cer types, safe, and pre­cise­ly tar­get­ed to the tu­mor site.

The pre­ci­sion of click chem­istry

A sim­ple yet in­cred­i­bly pow­er­ful sci­en­tif­ic ap­proach may be the key to un­lock­ing the hid­den po­ten­tial of can­cer ther­a­pies and im­prov­ing their ther­a­peu­tic in­dex. This con­cept is called “click chem­istry”, and it was first in­tro­duced in 2001 by Hart­muth Kolb, M.G. Finn, and No­bel prize win­ner Bar­ry Sharp­less.i It in­volves chem­i­cal re­ac­tions in which two mol­e­cules rapid­ly “click” with each oth­er, ig­nor­ing their sur­round­ings. When these types of re­ac­tions are con­duct­ed in a bi­o­log­i­cal set­ting, they are termed bioorthog­o­nal chem­istry, as there is no in­ter­fer­ence from or to na­tive bio­chem­i­cal process­es.

Bioorthog­o­nal chem­istry con­duct­ed in­side a hu­man body could open a door­way to im­prove the ther­a­peu­tic in­dex of chemother­a­peu­tics and un­lock new bi­o­log­i­cal ef­fects from can­cer med­i­cines” says Neal De­varaj, Pro­fes­sor of Chem­istry and Bio­chem­istry at UC San Diego and ad­vi­sor for Shasqi.

Pi­o­neer­ing click chem­istry in hu­mans

Shasqi, a clin­i­cal-stage biotech­nol­o­gy com­pa­ny, has cre­at­ed the Click Ac­ti­vat­ed Pro­to­drugs Against Can­cer (CA­PAC®) plat­form, which us­es click chem­istry to lo­cal­ize and ac­ti­vate a ‘pro­to­drug’ at the tu­mor site. Pro­to­drugs are at­ten­u­at­ed ver­sions of pow­er­ful can­cer ther­a­pies. When the pro­to­drugs reach the tu­mor, their ac­ti­va­tion leads to the re­lease of the full-strength pay­load (ac­tive drug) at the tu­mor site.

Shasqi’s first gen­er­a­tion ap­proach em­ploys an in­tra­tu­moral biopoly­mer in­jec­tion to lo­cal­ize the pro­to­drug ac­ti­va­tors at the tu­mor site. Shasqi’s lead as­set, SQ3370, is based on a dox­oru­bicin (Dox) pro­to­drug and has es­tab­lished click chem­istry in hu­mans. SQ3370 is well-tol­er­at­ed in pa­tients in a phase 1 study. De­spite dos­ing more than 10-times con­ven­tion­al Dox and up to 12 cy­cles, a max­i­mal­ly tol­er­at­ed dose has not been iden­ti­fied to date.

SQ3370 un­locks the op­por­tu­ni­ty to ex­ploit the full po­ten­tial of the drug class. Nov­el im­mune reg­u­la­to­ry ef­fects, as de­scribed pre­clin­i­cal­ly in 2021, were con­firmed in hu­mans. In­creased cy­to­tox­ic T-cell ac­tiv­i­ty ob­served at the high­er dose lev­els of SQ3370 (> 6-times the con­ven­tion­al Dox dose) in­di­cate im­mune ac­ti­va­tion, trend­ing to­wards an in­crease in tu­mor cell death in heav­i­ly pre­treat­ed pa­tients.

These find­ings es­tab­lish ex­cit­ing pos­si­bil­i­ties for SQ3370 and pave the way for ad­vanc­ing the pro­gram to Phase 2, which is cur­rent­ly en­rolling pa­tients. More im­por­tant­ly, they high­light how click chem­istry in hu­mans could one day tru­ly trans­form can­cer ther­a­pies and mo­ti­vate the de­vel­op­ment of new pro­to­drugs (e.g. au­ris­tatins, and tax­anes) as well as new tu­mor-tar­get­ing agents.

Click chem­istry and an­ti­bod­ies

An­ti­body drug con­ju­gates (AD­Cs) en­able the use of high­ly tox­ic and ef­fec­tive chemother­a­peu­tic agents by link­ing tu­mor-tar­get­ing an­ti­bod­ies to po­tent pay­loads. AD­Cs have im­proved the lives of many can­cer pa­tients, but clin­i­cal ap­pli­ca­tions re­main lim­it­ed due to nar­row ther­a­peu­tic in­dices and a lim­it­ed set of suit­able anti­gens that meet the cri­te­ria of AD­Cs.

By lo­cal­iz­ing click chem­istry ac­ti­va­tors to the tu­mor with an­ti­bod­ies, pro­to­drugs can be ac­ti­vat­ed and pay­loads re­leased at the tu­mor site. The CA­PAC plat­form de­cou­ples the tu­mor-tar­get­ing com­po­nent from the pay­load, spear­head­ing the pur­suit of non-in­ter­nal­iz­ing anti­gens.

This fea­ture ex­pands po­ten­tial tar­get anti­gens to those that do not re­side on the sur­face of tu­mor cells (e.g., in the tu­mor mi­croen­vi­ron­ment). These anti­gens rep­re­sent ex­cit­ing new tar­gets that are unique­ly suit­ed for click chem­istry in hu­mans. They hold great promise to ex­pand the in­di­ca­tions suit­able for an­ti­body-tar­get­ed ther­a­pies, es­pe­cial­ly with re­gards to sol­id tu­mors.

In ad­di­tion, sep­a­rat­ing the tu­mor-tar­get­ing com­po­nent from the pay­load en­ables unique ther­a­peu­tic com­bi­na­tions. A sin­gle tar­get­ing agent can be used with two or more pro­to­drugs, each ex­ploit­ing a dif­fer­ent mech­a­nism of ac­tion. These po­ten­tial reg­i­mens are cur­rent­ly in­ac­ces­si­ble due to over­lap­ping tox­i­c­i­ties.

Dis­rupt­ing can­cer ther­a­py as we know it

Im­prov­ing the ther­a­peu­tic in­dex of can­cer med­i­cines is one of the biggest chal­lenges we face to­day. Shasqi has un­locked click chem­istry in hu­mans and is poised to ap­ply the tech­nol­o­gy to cre­ate un­prece­dent­ed op­por­tu­ni­ties to ex­plore cu­ra­tive op­tions.

A key to ac­cel­er­at­ing the rate of progress against can­cer lies in col­lab­o­rat­ing to ac­ti­vate the un­tapped po­ten­tial of pow­er­ful can­cer ther­a­pies by lever­ag­ing the pre­ci­sion of click chem­istry.

“Bioorthog­o­nal chem­istry has the po­ten­tial to im­prove the util­i­ty and out­comes for many an­ti-can­cer treat­ment modal­i­ties. We see a fu­ture where com­bi­na­tions of ther­a­pies can be ac­ti­vat­ed at de­sired ar­eas of the body, re­sult­ing in much greater safe­ty and ef­fi­ca­cy than we have to­day” notes Car­olyn Bertozzi, Pro­fes­sor of Chem­istry at Stan­ford Uni­ver­si­ty and ad­vi­sor for Shasqi.


[i]Kolb, Finn, Sharp­less, Angew. Chem. Int. Ed. 2001, 40, 2004-2021.