BEIRUT, Lebanon — The killing on Wednesday of President Bashar al-Assad’s key security aides in a brazen bombing attack, close to Mr. Assad’s own residence, called into question the ability of a government that depends on an insular group of loyalists to function effectively as it battles a strengthening opposition.

The strike dealt a potent blow to the government, as much for where it took place as for the individuals who were targeted: the very cabinet ministers and intelligence chiefs who have coordinated the government’s iron-fisted approach to the uprising. The defense minister and the president’s brother-in-law were both killed, and others were seriously wounded.

The attack on the leadership’s inner sanctum as fighting raged in sections of the city for the fourth day suggested that the uprising had reached a decisive moment in the overall struggle for Syria. The battle for the capital, the center of Assad family power, appears to have begun. Though there was no indication he was wounded, Mr. Assad stayed out of public view — unusual but not unprecedented in a secretive country where the government has long tried to present an image of quiet control.

Image Daoud Rajha, left, Syria’s defense minister, and Asef Shawkat, President Bashar al-Assad’s brother-in-law, were killed on Wednesday in a bombing in Damascus. Credit... Left, Sana, via Reuters; right, Khaled Al-Hariri/Reuters

In Washington, Defense Secretary Leon E. Panetta said that Syria “is rapidly spinning out of control,” and warned Mr. Assad’s government to safeguard its large stockpile of chemical weapons. “It’s obvious what is happening in Syria is a real escalation,” he said at a joint news conference with the British defense minister, Philip Hammond.